Polo-like kinase inhibitors

ABSTRACT

Compounds of the following formula are provided for use with kinases: 
                         
wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/975,127, filed Sep. 25, 2007, and U.S. Provisional Application No.61/037,303, filed Mar. 17, 2008, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to inhibitkinases, as well as compositions of matter, kits and articles ofmanufacture comprising these compounds. The invention also relates tomethods for inhibiting kinases and treatment methods using compoundsaccording to the present invention. In addition, the invention relatesto methods of making the compounds of the present invention, as well asintermediates useful in such methods. In particular, the presentinvention relates to Polo-like Kinase (PLK) inhibitors, compositions ofmatter, kits and articles of manufacture comprising these compounds,methods for inhibiting PLK, and methods and intermediates useful formaking the inhibitors.

BACKGROUND OF THE INVENTION

The invention relates to inhibitors of enzymes that catalyze phosphoryltransfer and/or that bind ATP/GTP nucleotides, compositions comprisingthe inhibitors, and methods of using the inhibitors and inhibitorcompositions.

Many diseases states are characterized by the uncontrolled proliferationand differentiation of cells. These diseases states encompass a varietyof cell types and maladies such as cancer, atherosclerosis, restenosis,and psoriasis. Uncontrolled signaling due to defective control ofprotein phosphorylation has been implicated in a number of diseases anddisease conditions, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseaseand conditions of the central nervous system (CNS), cardiovasculardisease, dermatology, and angiogenesis.

The inhibitors and compositions comprising them are useful for treatingor modulating disease in which phosphoryl transferases, includingkinases, may be involved, symptoms of such disease, or the effect ofother physiological events mediated by phosphoryl transferases,including kinases. The invention also provides for methods of making theinhibitor compounds and methods for treating diseases in which one ormore phosphoryl transferase, including kinase, activities is involved.

Phosphoryl transferases are a large family of enzymes that transferphosphorous-containing groups from one substrate to another. By theconventions set forth by the Nomenclature Committee of the InternationalUnion of Biochemistry and Molecular Biology (IUBMB) enzymes of this typehave Enzyme Commission (EC) numbers starting with 2.7.-.- (See, BairochA., The ENZYME database in Nucleic Acids Res. 28:204-305 (2000)).Kinases are a class of enzymes that function in the catalysis ofphosphoryl transfer. The protein kinases constitute the largestsubfamily of structurally related phosphoryl transferases and areresponsible for the control of a wide variety of signal transductionprocesses within the cell. (See, Hardie, G. and Hanks, S. (1995) TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.).Protein kinases are thought to have evolved from a common ancestral genedue to the conservation of their structure and catalytic function.Almost all kinases contain a similar 250-300 amino acid catalyticdomain. The protein kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, histidine, etc.). Protein kinase sequencemotifs have been identified that generally correspond to each of thesekinase families (See, for example, Hanks, S. K.; Hunter, T., FASEB J.9:576-596 (1995); Kinghton et al., Science, 253:407-414 (1991); Hiles etal., Cell 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993);Garcia-Bustosi et al., EMBO J., 13:2352-2361 (1994)). Lipid kinases(e.g. PI3K) constitute a separate group of kinases with structuralsimilarity to protein kinases.

Protein and lipid kinases regulate many different cell processesincluding, but not limited to, proliferation, growth, differentiation,metabolism, cell cycle events, apoptosis, motility, transcription,translation and other signaling processes, by adding phosphate groups totargets such as proteins or lipids. Phosphorylation events catalyzed bykinases act as molecular on/off switches that can modulate or regulatethe biological function of the target protein. Phosphorylation of targetproteins occurs in response to a variety of extracellular signals(hormones, neurotransmitters, growth and differentiation factors, etc.),cell cycle events, environmental or nutritional stresses, etc. Proteinand lipid kinases can function in signaling pathways to activate orinactivate, or modulate the activity of (either directly or indirectly)the targets. These targets may include, for example, metabolic enzymes,regulatory proteins, receptors, cytoskeletal proteins, ion channels orpumps, or transcription factors. Initial interest in protein kinases aspharmacological targets was stimulated by the findings that many viraloncogenes encode structurally modified cellular protein kinases withconstitutive enzyme activity. These findings pointed to the potentialinvolvement of oncogene related protein kinases in human proliferativesdisorders. Subsequently, deregulated protein kinase activity, resultingfrom a variety of more subtle mechanisms, has been implicated in thepathophysiology of a number of important human disorders including, forexample, cancer, CNS conditions, and immunologically related diseases.The development of selective protein kinase inhibitors that can blockthe disease pathologies and/or symptoms resulting from aberrant proteinkinase activity has therefore generated much interest.

Cancer results from the deregulation of the normal processes thatcontrol cell division, differentiation and apoptotic cell death. Proteinkinases play a critical role in this regulatory process. A partialnon-limiting list of such kinases includes ab1, Aurora-A, Aurora-B,Aurora-C, Akt, bcr-abl, Blk, Brk, Btk, c-Kit, c-Met, c-Src, CDK1, CDK2,CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB4, ERK, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Flt-4, Flt-1, FER, Frk, Fyn, Hck,IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PLKs,PYK2, Ros, Tie1, Tie2, Trk, Yes and Zap70. In mammalian biology, suchprotein kinases comprise mitogen activated protein kinase (MAPK)signaling pathways. MAPK signaling pathways are inappropriatelyactivated by a variety of common disease-associated mechanisms such asmutation of ras genes and deregulation of growth factor receptors(Magnuson et al., Seminars in Cancer Biology 5:247-252 (1994)).Therefore the inhibition of protein kinases is an object of the presentinvention.

Polo-like kinases (PLKs including PLK1, PLK2, PLK3 and PLK4) areserine/threonine protein kinases that have been implicated in humancancer, such as colon, breast and other solid tumors. Polo-like kinases(also referred to as PLKs) are believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically, PLK1may play a role in controlling the accurate segregation of chromosomesduring mitosis. Misregulation of the cell cycle can lead to cellularproliferation and other abnormalities. In human colon cancer tissue,PLKs have been found to be overexpressed (See, Barr et al in Nat. Rev.Mol. Cell. Biol. 5: 429 (2004); van Vugt et al in Oncogene, 24: 2844(2005)). PLK1 as an attractive candidate molecule for targeted tumortherapy is reported recently (see Takai et al in Oncogene, 24:287(2005); McInnes et al in Current Topics in Med. Chem., 5: 181 (2005)).

There is a continued need to find new therapeutic agents to treat humandiseases. Protein kinases, specifically but not limited to Polo-likeKinase (PLK), are especially attractive targets for the discovery of newtherapeutics due to their important role in hyperproliferativedisorders; cancer (e.g., solid tumors, leukemias, lymphomas, non-smallcell lung cancers and esophageal carcinomas); inflammatory andautoimmune diseases (e.g., psoriasis, alopecia; multiple sclerosis;colitis, arthritis, Alzheimer's disease, glomerulonephritis and woundhealing); chemotherapy agent-induced alopecia and mucositis;cardiovascular diseases (e.g., stenoses, arterioscleroses, restenoses,and hypertrophy); viral, bacterial, fungal and/or parasitic infectiousdiseases (e.g., cytomegalici infections, herpes, hepatitis B and C,Karposi's sarcoma, HIV diseases); nephrological diseases (e.g.,glomerulonephritis); chronic and acute neurodegenerative diseases (e.g.,Huntington's disease, amyotrophic lateral sclerosis, Parkinson'sdisease, AIDS dementia, Alzheimer's disease, ischemias of the brain andneurotraumas); skin diseases (e.g., psoriasis); bone diseases; theprotection of proliferating cells (e.g., hair, intestinal, blood andprogenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment; and other diseases. Certain inhibitors ofPLK are disclosed in WO 2007/095188. The present invention providesinhibitors of PLKs, including some having reduced susceptibility tomulti-drug resistance.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting kinases. The present invention also provides compositions,articles of manufacture and kits comprising these compounds. Inaddition, the invention relates to methods of making the compounds ofthe present invention, as well as intermediates useful in such methods.

In one embodiment, a pharmaceutical composition is provided thatcomprises a kinase inhibitor according to the present invention as anactive ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more inhibitorsof this invention. These pharmaceutical compositions may be administeredor coadministered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or coadministered in slow release dosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with kinases.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one kinase inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one kinase inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit kinases. In particular, the compounds,compositions, kits and articles of manufacture can be used to inhibit aPLK.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which kinases possessactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound is administered to a subject whereinkinase activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitskinase.

In another embodiment, a method of inhibiting kinase is provided thatcomprises contacting a kinase with a compound according to the presentinvention.

In another embodiment, a method of inhibiting kinase is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit kinase in vivo.

In another embodiment, a method of inhibiting a kinase is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits kinasein vivo. It is noted that the compounds of the present invention may bethe first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of treating a condition in a patientthat is known to be mediated by kinases, or which is known to be treatedby kinase inhibitors, comprising administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method is provided for treating a disease statefor which a kinase possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which a kinase possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which a kinase possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby a kinase, or that is known to be treated by kinase inhibitors.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers, and geometricisomers), independent of whether the compound is present as anindividual stereoisomer or a mixture of stereoisomers. Further, unlessotherwise specified, recitation of a compound is intended to encompassall possible resonance forms and tautomers. With regard to the claims,the language “compound comprising the formula,” “compound having theformula” and “compound of the formula” is intended to encompass thecompound and all pharmaceutically acceptable ionized forms and solvates,all possible stereoisomers, and all possible resonance forms andtautomers unless otherwise specifically specified in the particularclaim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting kinase and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have kinase inhibitory activity.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates SEQ. ID Nos. 1-6 referred to in this application.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A (2000) and B(2001), Plenum Press, New York. Also, unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with (C₃₋₈) rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene. Furtherexamples of alicyclic moieties include tetrahydrofuran, pyrrolidine,piperidine, piperazine, morpholine, and the like.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀)alkenylene, a (C₂₋₁₅)alkenylene, a (C₂₋₁₀)alkenylene, a(C₂₋₅)alkenylene or a (C₂₋₃)alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a(C₂)alkenylene, a (C₃)alkenylene or a (C₄)alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.When substituted particular groups for alkoxy include substituentsindependently selected from the group consisting of amino, (C₁₋₄)alkoxy,(C₁₋₄)alkyl, cyano, (C₃₋₈)cycloalkyl, halo, hydroxy, nitro, oxo, andoptionally substituted phenyl. An optionally substituted (C₁₋₄)alkoxyhas from 1 to 6 such substituents.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with one or more of the carbon atoms being replaced withoxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl”), sulfur (See“thioalkyl”), and/or nitrogen (See “azaalkyl”). (C_(X))alkyl and(C_(X-Y))alkyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, (C₁₋₆)alkyl includes alkyls thathave a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl and thelike) means a straight or branched, saturated or unsaturated aliphaticdivalent radical having the number of atoms indicated or when no atomsare indicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes,benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like). In particular embodiments, “alkyl,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl, a (C₁₋₅)alkyl, a(C₁₋₄)alkyl or a (C₁₋₃)alkyl. Alternatively, “alkyl,” either alone orrepresented along with another radical, can be a (C₁)alkyl, a (C₂)alkylor a (C₃)alkyl. When substituted particular groups for alkyl includesubstituents independently selected from the group consisting of amino,(C₁₋₄)alkoxy, (C₁₋₄)alkyl, amido, carboxy, cyano, (C₃₋₈)cycloalkyl,halo, hydroxy, nitro, oxo, an ester of phosphoric (—OP(O)(OH)₂) acid,and optionally substituted phenyl. An optionally substituted (C₁₋₄)alkylor (C₁₋₁₀)alkyl has from 1 to 6 such substituents.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀)alkynylene, a (C₂₋₁₅)alkynylene, a(C₂₋₁₀)alkynylene, a (C₂₋₅)alkynylene or a (C₂₋₃)alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂)alkynylene, a (C₃)alkynylene or a(C₄)alkynylene.

“Amido” means the radical —C(═O)—NR—, —C(═O)—NRR′, —NR—C(═O)— and/or—NR—C(═O)R′, wherein each R and R′ are independently hydrogen or afurther substituent. R when attached to nitrogen is typically selectedfrom the group consisting of hydrogen and (C₁₋₄)alkyl. R′ when attachedto nitrogen is typically selected from the group consisting of alkyl,cycloalkyl, and heterocycloalkyl, each unsubstituted or substituted.Where R′ is a substituted (C₁₋₄)alkyl typical substituents thereon are(C₁₋₄)alkoxy, amido, carboxy, cyano, (C₃₋₈)cycloalkyl, halo, hydroxy,nitro, oxo, and optionally substituted phenyl. Where R′ is a substituted(C₃₋₈)cycloalkyl typical substituents thereon are (C₁₋₄)alkoxy,(C₁₋₄)alkyl, amido, carboxy, cyano, halo, hydroxy, nitro, oxo, andoptionally substituted phenyl. Where R′ is a substitutedhetero(C₃₋₆)cycloalkyl typical substituents thereon are (C₁₋₄)alkoxy,(C₁₋₄)alkyl, amido, carboxy, cyano, (C₃₋₈)cycloalkyl, halo, hydroxy,nitro, oxo, and optionally substituted phenyl.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, —NH(cycloalkyl), —NH(heterocycloalkyl), andthe like and the further substituents on the nitrogen can themselves besubstituted or unsubstituted. Where a further substituent is (C₁₋₄)alkyltypical substituents thereon are (C₁₋₄)alkoxy, amido, carboxy, cyano,(C₃₋₈)cycloalkyl, halo, hydroxy, nitro, oxo, and optionally substitutedphenyl. Where a further substituent is (C₃₋₈)cycloalkyl typicalsubstituents thereon are (C₁₋₄)alkoxy, (C₁₋₄)alkyl, amido, carboxy,cyano, halo, hydroxy, nitro, oxo, and optionally substituted phenyl.Where a further substituent is hetero(C₃₋₆)cycloalkyl typicalsubstituents thereon are (C₁₋₄)alkoxy, (C₁₋₄)alkyl, amido, carboxy,cyano, (C₃₋₈)cycloalkyl, halo, hydroxy, nitro, oxo, and optionallysubstituted phenyl. Optionally, the two substituents together with thenitrogen may also form a ring. Unless indicated otherwise, the compoundsof the invention containing amino moieties may include protectedderivatives thereof. Suitable protecting groups for amino moietiesinclude acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated, conjugated ring system, either having total number of pielectrons is equal to 4n+2 or having aromatic character or having themaximum number of double bonds. An aromatic ring may be such that thering atoms are only carbon atoms or may include carbon and non-carbonatoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (C_(X))aryl and (C_(X-Y))aryl are typically used whereX and Y indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl. Particular aryls arephenyl and naphthyl. When substituted particular groups for aryl includesubstituents independently selected from the group consisting of amino,optionally substituted (C₁₋₄)alkoxy, optionally substituted (C₁₋₄)alkyl,amido, carboxy, cyano, (C₃₋₈)cycloalkyl, halo, hydroxy, and nitro. Anoptionally substituted (C₄₋₁₂)aryl has from 1 to 4 such substituents.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl, (C₇₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl.Alternatively, “bicycloalkyl,” either alone or represented along withanother radical, can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a(C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyloxy” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carbonyloxy” means the radical R—C(═O)O— where the substituent isattached through oxygen and R is hydrogen or further substituents,particularly optionally substituted (C₁₋₄)alkyl or optionallysubstituted phenyl.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₁₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl. When substituted particular groupsfor cycloalkyl include substituents independently selected from thegroup consisting of amino, optionally substituted (C₁₋₄)alkoxy,optionally substituted (C₁₋₄)alkyl, amido, carboxy, cyano, halo,hydroxy, nitro, oxo, an ester of phosphoric (—OP(O)(OH)₂) acid, andoptionally substituted phenyl. An optionally substituted (C₃₋₈)alkyl hasfrom 1 to 5 such substituents.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene, a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease,” “disorder” and “condition” specifically includes anyunhealthy condition of an animal or part thereof and includes anunhealthy condition that may be caused by, or incident to, medical orveterinary therapy applied to that animal, i.e., the “side effects” ofsuch therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,thiophene, pyrrole, imidazole, isothiazole, isoxazole, oxadiazole,oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, 2-oxoindoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone, benzo[b][1,4]oxazine, benzo[b][1,4]oxazin-3(4H)-one,benzo[d][1,3]dioxole, 2,2-difluorobenzo[d][1,3]dioxole. The bicyclic ortricyclic heteroaryl rings can be attached to the parent moleculethrough either the heteroaryl group itself or the aryl, cycloalkyl,cycloalkenyl or heterocycloalkyl group to which it is fused. Theheteroaryl groups of this invention can be substituted or unsubstituted.In particular embodiments, “heteroaryl,” either alone or representedalong with another radical, can be a hetero(C₁₋₁₀)aryl,hetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl. When substitutedparticular groups for heteroaryl include substituents independentlyselected from the group consisting of amino, optionally substituted(C₁₋₄)alkoxy, optionally substituted (C₁₋₄)alkyl, amido, carboxy, cyano,(C₃₋₈)cycloalkyl, halo, hydroxy, and nitro. An optionally substitutedhetero(C₁₋₁₀)aryl has from 1 to 4 such substituents. It is understoodthat nitrogen containing heteroaryls may be substituted on nitrogen,particularly with optionally substituted (C₁₋₄)alkoxy, optionallysubstituted (C₁₋₄)alkyl, carboxy, and optionally substituted phenyl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(O—)═, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloaryl or a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S. Non-exclusive examples ofheterocycloalkyl include azetidinyl, piperidyl, morpholyl, piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,tetrahyrofuranyl, 1,3-dioxanyl, 1,4-dioxanyl and the like. In particularembodiments, “heterocycloalkyl,” either alone or represented along withanother radical, can be a hetero(C₁₋₁₃)cycloalkyl, ahetero(C₁₋₉)cycloalkyl, a hetero(C₁₋₆)cycloalkyl, ahetero(C₅₋₉)cycloalkyl or a hetero(C₂₋₆)cycloalkyl or ahetero(C₃₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl. When substitutedparticular groups for heterocycloalkyl include substituentsindependently selected from the group consisting of amino, optionallysubstituted (C₁₋₄)alkoxy, optionally substituted (C₁₋₄)alkyl, amido,carboxy, cyano, halo, hydroxy, nitro, oxo, an ester of phosphoric(—OP(O)(OH)₂) acid, and optionally substituted phenyl. An optionallysubstituted hetero(C₃₋₆)alkyl has from 1 to 5 such substituents. It isunderstood that nitrogen containing heterocycloalkyls may be substitutedon nitrogen, particularly with optionally substituted (C₁₋₄)alkoxy,optionally substituted (C₁₋₄)alkyl, carboxy, and optionally substitutedphenyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent, particularlyoptionally substituted (C₁₋₄)alkyl.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n−1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Moiety providing X atom separation” and “linker providing X atomseparation” between two other moieties mean that the chain of atomsdirectly linking the two other moieties is X atoms in length. When X isgiven as a range (e.g., X₁-X₂), then the chain of atoms is at least X₁and not more than X₂ atoms in length. It is understood that the chain ofatoms can be formed from a combination of atoms including, for example,carbon, nitrogen, sulfur and oxygen atoms. Further, each atom canoptionally be bound to one or more substituents, as valencies allow. Inaddition, the chain of atoms can form part of a ring. Accordingly, inone embodiment, a moiety providing X atom separation between two othermoieties (R and R′) can be represented by R-(L)_(X)-R′ where each L isindependently selected from the group consisting of CR″R′″, NR″″, O, S,CO, CS, C═NR′″″, SO, SO₂, and the like, where any two or more of R″,R′″, R″″ and R′″″ can be taken together to form a substituted orunsubstituted ring. The linker is intended to result in stablecompounds. Here the term stable means compounds that are notsubstantially altered by production, recovery, and storage. Excludedfrom the term, unless otherwise noted, are peroxides, thioperoxides,ketals, animals, ketenes and the like.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxo” means refers to a carbon atom substituted with a double bondedoxygen, to give a carbonyl group which may, depending on the othersubstituents attached, be the carbonyl group of an aldehyde, ketone,ester, amide, or acid.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid, or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable in the amounts used and includesthat which is acceptable for veterinary use as well as humanpharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable. Such saltsinclude acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Optionally substituted phenyl” refers to a phenyl group optionallyhaving 1 to 5 substituents independently selected from the groupconsisting of amino, optionally substituted C₁₋₄ alkyl, optionallysubstituted)C₁₋₄)alkoxy, amido, amino, carboxy, cyano, halogen,hydroxyl, and nitro.

“Oxycarbonyl” means the radical R—O(═O)C— where the substituent isattached through carbon and R is further substituents, particularlyoptionally substituted (C₁₋₄)alkyl.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, tartrates,malonates, oxalates, salicylates, propionates, succinates, fumarates,maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,esters of amino acids, and the like. Similarly, a compound comprising anamine group may be administered as an amide that is converted byhydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” includes humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like). A particular subject orpatient is a human.

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(CH₃)₃C—OCO—], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; CH₃CH(NH₂)CO—), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),His (histidine), Ile (isoleucine), Leu (leucine; (CH₃)₂CHCH₂CH(NH₂)CO—),Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val(valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline),5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitableprotecting groups include those typically employed in peptide synthesis,including acyl groups (such as formyl and acetyl), arylmethyloxycarbonylgroups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl),t-butoxycarbonyl groups [(CH₃)₃C—OCO—], and the like. Suitable peptideresidues include peptide residues comprising two to five, and optionallytwo to three, of the aforesaid amino acid residues. Examples of suchpeptide residues include, but are not limited to, residues of suchpeptides as Ala-Ala [CH₃CH(NH₂)CO—NHCH(CH₃)CO—], Gly-Phe, Nva-Nva,Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu.The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixturesthereof. In addition, the amino acid or peptide residue may have anasymmetric carbon atom. Examples of suitable amino acid residues havingan asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva,Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetriccarbon atom include peptide residues having one or more constituentamino acid residues having an asymmetric carbon atom. Examples ofsuitable amino acid protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH₃)₃C—OCO—], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl andβ-iodoethoxycarbonyl).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃—In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amido, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyloxy, carbocyclyl,carboxyl, carbonyl group, carbonyloxy, cycloalkyl, cycloalkylene, ester,halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl,heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, imino, iminoketone,ketone, nitro, oxycarbonyl, oxaalkyl, and oxoalkyl moieties, each ofwhich may optionally also be substituted or unsubstituted. In oneparticular embodiment, examples of substituents include, but are notlimited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl. In addition, thesubstituent is itself optionally substituted by a further substituent.In one particular embodiment, examples of the further substituentinclude, but are not limited to, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent, particularly (C₁₋₄)alkyl and optionallysubstituted phenyl. It is noted that the sulfinyl radical may be furthersubstituted with a variety of substituents to form different sulfinylgroups including sulfinic acids, sulfinamides, sulfinyl esters, andsulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent, particularly (C₁₋₄)alkyl and optionallysubstituted phenyl. It is noted that the sulfonyl radical may be furthersubstituted with a variety of substituents to form different sulfonylgroups including sulfonic acids, sulfonamides, sulfonate esters, andsulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” or “treat” means any administration of acompound of the present invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology) and includes allprocesses providing slowing, interrupting, arresting, controlling, orstopping of the progression of the conditions described herein, but doesnot necessarily indicate a total elimination of all symptoms or a cureof the disease.

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to inhibitkinases and, in particular, Polo-like Kinases (referred to herein asPLKs). The present invention also relates to pharmaceuticalcompositions, kits and articles of manufacture comprising suchcompounds. In addition, the present invention relates to methods andintermediates useful for making the compounds. Further, the presentinvention relates to methods of using said compounds. It is noted thatthe compounds of the present invention may also possess activity forother members of the same protein family and thus may be used to addressdisease states associated with these other family members.

Disregulation of PLKs is implicated in such areas as hyperproliferativedisorders; cancer (e.g., solid tumors, leukemias, lymphomas, non-smallcell lung cancers and esophageal carcinomas); inflammatory andautoimmune diseases (e.g., psoriasis, alopecia; multiple sclerosis;colitis, arthritis, Alzheimer's disease, glomerulonephritis and woundhealing); chemotherapy agent-induced alopecia and mucositis;cardiovascular diseases (e.g., stenoses, arterioscleroses, restenoses,and hypertrophy); viral, bacterial, fungal and/or parasitic infectiousdiseases (e.g., cytomegalic infections, herpes, hepatitis B and C,Karposi's sarcoma, HIV diseases); nephrological diseases (e.g.,glomerulonephritis); chronic and acute neurodegenerative diseases (e.g.,Huntington's disease, amyotrophic lateral sclerosis, Parkinson'sdisease, AIDS dementia, Alzheimer's disease, ischemias of the brain andneurotraumas); skin diseases (e.g., psoriasis); bone diseases; theprotection of proliferating cells (e.g., hair, intestinal, blood andprogenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment.

It is noted that the compounds of the present invention may also possessinhibitory activity for other protein kinase family members and thus maybe used to address disease states associated with these other familymembers.

Polo-Like Kinase Inhibitors

In one embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   W is selected from the group consisting of CR₈ and N;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₇ and the nitrogen to which L is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃₂ and R₃₃ are taken together to form X, or R₃₂ and R₃₃ are        each independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   X is selected from the group consisting of C—R₄₀, NR₁₄, O, and S        or any two R₂, R₅, R₆, R₉, R₁₀ R₃₂ and R₃₃ are taken together to        form a substituted or unsubstituted ring;    -   p is selected from the group consisting of 0 and 1;    -   R₃₄ is selected from the group consisting of —CONJ₃₄-, —NJ₃₄        CO—, —NJ₃₄-, —SO₂NJ₃₄-, —NJ₃₄ SO₂—,    -   J₃₄ is selected from the group consisting of hydrogen and        (C₁₋₄)alkyl;    -   R₃₅ is selected from the group consisting of amino, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₃₋₈)cycloalkyl, hetero(C₃₋₆)cycloalkyl,        (C₇₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, each substituted        or unsubstituted;    -   q is selected from the group consisting of 0 and 1;    -   R₃₆ is selected from the group consisting of is selected from        the group consisting (C₁₋₄)alkyl, (C₁₋₄)azaalkyl,        (C₃₋₈)cycloalkyl, hetero(C₃₋₈)cycloalkyl, each substituted or        unsubstituted;    -   r is selected from the group consisting of 0 and 1;    -   R₃₇ is optionally substituted (C₃₋₈)cycloalkyl, when R₃₆ is        selected from the group consisting of optionally substituted        (C₁₋₄)alkyl and optionally substituted (C₁₋₄)azaalkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl, when R₃₆ is selected        from the group consisting of optionally substituted        (C₃₋₈)cycloalkyl and optionally substituted        hetero(C₃₋₈)cycloalkyl; and    -   R₄₀ is selected from the group consisting of dihydrogen, halo,        nitro, cyano, (C₁₋₁₀)alkoxy, and (C₁₋₁₀)alkyl.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₇ and the nitrogen to which L is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   or any two R₅, R₆, R₉ and R₁₀ and are taken together to form a        substituted or unsubstituted ring.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group,    -   or any two R₅, R₆, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In yet another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In still a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5 (it        being understood that m−2 is m as defined here minus 2);    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) and R_(17b) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbamoyloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido, imino,        sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₈ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   X is O;    -   L is absent;    -   m is selected from the group consisting of 2 and 3;    -   R₁₇ is halo; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        and optionally substituted alkoxy; and    -   R₁₈ is amino.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   X is O;    -   L is absent;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        and optionally substituted alkoxy;    -   R_(17b) is selected from the group consisting of hydrogen and        halo; and    -   R₁₈ is amino.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In yet another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group; and    -   R₂₁ and R₂₂ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   or any two R₅, R₆, R₁₅, R₁₆, R₂₁ and R₂₂ are taken together to        form a substituted or unsubstituted ring.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In still a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group,    -   or any two R₅, R₆, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In yet another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) and R_(17b) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbamoyloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido, imino,        sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₈ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group; and    -   R₂₁ and R₂₂ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   or any two R₅, R₆, R₁₅, R₁₆, R₂₁ and R₂₂ are taken together to        form a substituted or unsubstituted ring.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In yet another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group,    -   or any two R₆, R₁₅ and R₁₆ are taken together to form a        substituted or unsubstituted ring.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In still a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) and R_(17b) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbamoyloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido, imino,        sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₈ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2 and 3;    -   R₁₇ is halo; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        and optionally substituted alkoxy; and    -   R₁₈ is amino.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   X is O;    -   L is absent;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        and optionally substituted alkoxy;    -   R_(17b) is selected from the group consisting of hydrogen and        halo; and    -   R₁₈ is amino.

In yet another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In still a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group; and    -   R₂₁ and R₂₂ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   or any two R₆, R₁₅, R₁₆, R₂₁ and R₂₂ are taken together to form        a substituted or unsubstituted ring.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₅ and R₁₆ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In another embodiment, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof.

In still another embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof.

It is understood that when p is 0 all of R₃₄, R₃₅, R₃₆, and R₃₇ areabsent.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is 1;    -   L is absent;    -   R₁ is selected from the group consisting of hydrogen, alkoxy,        and (C₁₋₄)alkyl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₄)alkyl, and (C₃₋₈)cycloalkyl, each substituted or        unsubstituted;    -   R₇ is optionally substituted (C₄₋₁₂)aryl;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, and optionally substituted        (C₁₋₄)alkyl;    -   X is selected from the group consisting of O and S;    -   p is selected from the group consisting of 0 and 1;    -   R₃₄ is —CONJ₃₄;    -   J₃₄ is selected from the group consisting of hydrogen and        (C₁₋₄)alkyl;    -   R₃₅ is selected from the group consisting of (C₃₋₈)cycloalkyl,        hetero(C₃₋₆)cycloalkyl, (C₇₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, each substituted or unsubstituted;    -   q is selected from the group consisting of 0 and 1;    -   R₃₆ is selected from the group consisting of is selected from        the group consisting (C₁₋₄)alkyl, (C₃₋₈)cycloalkyl,        hetero(C₃₋₈)cycloalkyl, each substituted or unsubstituted;    -   r is selected from the group consisting of 0 and 1;    -   R₃₇ is optionally substituted (C₃₋₈)cycloalkyl, when R₃₆ is        optionally substituted (C₁₋₄)alkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl, when R₃₆ is selected        from the group consisting of optionally substituted        (C₃₋₈)cycloalkyl and optionally substituted        hetero(C₃₋₈)cycloalkyl.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

and the pharmaceutically acceptable salts thereof;

-   -   Y is —(CR₉R₁₀)_(n)—;    -   n is 1;    -   L is absent;    -   R₁ is selected from the group consisting of hydrogen, alkoxy,        and (C₁₋₄)alkyl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₄)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₄)alkyl, and (C₃₋₈)cycloalkyl, each substituted or        unsubstituted;    -   R₇ is (C₄₋₁₂)aryl, optionally substituted with from 1 to 4        groups independently selected from the group consisting of        consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy, cyano, halogen,        hydroxyl, nitro, and trifluoromethyl;    -   R₉ and R₁₀ are hydrogen;    -   p is selected from the group consisting of 0 and 1;    -   R₃₄ is —CONJ₃₄;    -   J₃₄ is selected from the group consisting of hydrogen and        (C₁₋₄)alkyl;    -   R₃₅ is selected from the group consisting of (C₃₋₈)cycloalkyl,        hetero(C₃₋₆)cycloalkyl, (C₇₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, each substituted or unsubstituted;    -   q is selected from the group consisting of 0 and 1;    -   R₃₆ is selected from the group consisting of is selected from        the group consisting (C₁₋₄)alkyl, (C₃₋₈)cycloalkyl,        hetero(C₃₋₈)cycloalkyl, each substituted or unsubstituted;    -   r is selected from the group consisting of 0 and 1;    -   R₃₇ is optionally substituted (C₃₋₈)cycloalkyl, when R₃₆ is        optionally substituted (C₁₋₄)alkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl, when R₃₆ is selected        from the group consisting of optionally substituted        (C₃₋₈)cycloalkyl and optionally substituted        hetero(C₃₋₈)cycloalkyl.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

and the pharmaceutically acceptable salts thereof;

-   -   Y is —(CR₉R₁₀)_(n)—;    -   n is 1;    -   L is absent;    -   R₁ is selected from the group consisting of hydrogen, alkoxy,        and (C₁₋₄)alkyl, each substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₄)alkyl, and (C₃₋₁₂)cycloalkyl, each substituted or        unsubstituted;    -   R₇ is (C₄₋₁₂)aryl, optionally substituted with from 1 to 4        groups independently selected from the group consisting of        consisting of (C₁₋₄)alkyl, (C₁₋₄)alkoxy, cyano, halogen,        hydroxyl, nitro, and trifluoromethyl;    -   R₉ and R₁₀ are hydrogen;    -   p is 1;    -   R₃₄ is selected from the group consisting of —CONJ₃₄;    -   J₃₄ is selected from the group consisting of hydrogen and        (C₁₋₄)alkyl;    -   p is 1;    -   R₃₅ is selected from the group consisting of optionally        substituted (C₃₋₈)cycloalkyl;    -   q is 1;    -   R₃₆ is optionally substituted hetero(C₃₋₈)cycloalkyl;    -   r is 1; and    -   R₃₇ is optionally substituted (C₁₋₄)alkyl.

In yet a further embodiment, PLK inhibitors of the present inventioncomprise:

and the pharmaceutically acceptable salts thereof;

-   -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ are taken together to        form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   or any two R₂, R₅, R₆, R₉, and R₁₀ are taken together to form a        substituted or unsubstituted ring;    -   p is selected from the group consisting of 0 and 1;    -   R₃₄ is selected from the group consisting of —CONJ₃₄-, —NJ₃₄        CO—, —NJ₃₄-, —SO₂NJ₃₄-, —NJ₃₄SO₂—,    -   J₃₄ is selected from the group consisting of hydrogen and        (C₁₋₄)alkyl;    -   R₃₅ is selected from the group consisting of amino, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₃₋₈)cycloalkyl, hetero(C₃₋₆)cycloalkyl,        (C₇₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, each substituted        or unsubstituted;    -   q is selected from the group consisting of 0 and 1;    -   R₃₆ is selected from the group consisting of is selected from        the group consisting (C₁₋₄)alkyl, (C₁₋₄)azaalkyl,        (C₃₋₈)cycloalkyl, hetero(C₃₋₈)cycloalkyl, each substituted or        unsubstituted;    -   r is selected from the group consisting of 0 and 1;    -   R₃₇ is optionally substituted (C₃₋₈)cycloalkyl, when R₃₆ is        selected from the group consisting of optionally substituted        (C₁₋₄)alkyl and optionally substituted (C₁₋₄)azaalkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl, when R₃₆ is selected        from the group consisting of optionally substituted        (C₃₋₈)cycloalkyl and optionally substituted        hetero(C₃₋₈)cycloalkyl;    -   R₃₈ is fluoro or chloro;    -   s is selected from the group consisting of 0, 1, 2, 3, and 4;        and    -   R₃₉ is independently selected from the group consisting of        amino, optionally substituted (C₁₋₄)alkoxy, optionally        substituted (C₁₋₄)alkyl, amido, carboxy, cyano,        (C₃₋₈)cycloalkyl, halo, hydroxy, and nitro.

Such compounds are expected to have reduced susceptibility to multi-drugresistant tumors.

In particular, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof;    -   n is 1;    -   Y is —(CR₉R₁₀)_(n)—;    -   R₁ is selected from the group consisting of hydrogen,        (C₁₋₄)alkoxy, and (C₁₋₄)alkyl, each substituted or        unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, and (C₃₋₁₂)cycloalkyl, each substituted or        unsubstituted;    -   R₉ and R₁₀ are hydrogen;    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃₈ is selected from the group consisting of fluoro and chloro;    -   s is selected from the group consisting of 0, 1, 2, 3, and 4;    -   each R₃₉ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        alkoxy, aryloxy, heteroaryloxy, carbamoyloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        carboxyamino, ureido, imino, sulfonyl, aminosulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In particular, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof;    -   n is 1;

Y is —(CR₉R₁₀)_(n)—;

-   -   R₁ is selected from the group consisting of hydrogen,        (C₁₋₄)alkoxy, and (C₁₋₄)alkyl, each substituted or        unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;

R₅ is selected from the group consisting of hydrogen and halo;

-   -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, and (C₃₋₁₂)cycloalkyl, each substituted or        unsubstituted;    -   R₉ and R₁₀ are hydrogen;    -   R₁₉ is hydrogen;    -   R₂₀ optionally substituted hetero(C₃₋₁₂)cycloalkyl;    -   R₃₈ is selected from the group consisting of fluoro and chloro;    -   s is selected from the group consisting of 0, 1, 2, 3, and 4;    -   each R₃₉ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, (C₁₋₄)alkoxy, (C₁₋₄)alkyl, each        substituted or unsubstituted.

In particular, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof;    -   n is 1;    -   Y is —(CR₉R₁₀)_(n)—;    -   R₁ is selected from the group consisting of hydrogen,        (C₁₋₄)alkoxy, and (C₁₋₄)alkyl, each substituted or        unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, and (C₃₋₁₂)cycloalkyl, each substituted or        unsubstituted;    -   R₉ and R₁₀ are hydrogen;    -   R₃₅ is selected from the group consisting of (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₃₋₈)cycloalkyl, hetero(C₃₋₈)cycloalkyl,        (C₇₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, each substituted        or unsubstituted;    -   R₃₆ is selected from the group consisting of is selected from        the group consisting (C₁₋₄)alkyl, (C₁₋₄)azaalkyl,        (C₃₋₈)cycloalkyl, hetero(C₃₋₈)cycloalkyl, each substituted or        unsubstituted;    -   R₃₇ is optionally substituted (C₃₋₈)cycloalkyl, when R₃₆ is        selected from the group consisting of optionally substituted        (C₁₋₄)alkyl and optionally substituted (C₁₋₄)azaalkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl, when R₃₆ is selected        from the group consisting of optionally substituted        (C₃₋₈)cycloalkyl and optionally substituted        hetero(C₃₋₈)cycloalkyl;    -   R₃₈ is selected from the group consisting of fluoro and chloro;    -   s is selected from the group consisting of 0, 1, 2, 3, and 4;    -   each R₃₉ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, (C₁₋₄)alkoxy, (C₁₋₄)alkyl,        aryl(C₁₋₁₀)alkyl, and hetero(C₁₋₁₀)aryl.

In particular, PLK inhibitors of the present invention comprise:

-   -   and the pharmaceutically acceptable salts thereof;    -   n is 1;    -   Y is —(CR₉R₁₀)_(n)—;    -   R₁ is selected from the group consisting of hydrogen,        (C₁₋₄)alkoxy, and (C₁₋₄)alkyl, each substituted or        unsubstituted;    -   R₂ is selected from the group consisting of hydrogen and        optionally substituted (C₁₋₁₀)alkyl;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen and halo;    -   R₆ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, and (C₃₋₁₂)cycloalkyl, each substituted or        unsubstituted;    -   R₉ and R₁₀ are hydrogen;    -   R₃₅ is selected optionally substituted (C₃₋₈)cycloalkyl;    -   R₃₆ is optionally substituted hetero(C₃₋₈)cycloalkyl;    -   R₃₇ is optionally substituted (C₁₋₄)alkyl;    -   R₃₈ is selected from the group consisting of fluoro and chloro;    -   s is selected from the group consisting of 0, 1, and 2;        each R₃₉ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, (C₁₋₄)alkoxy, (C₁₋₁₄)alkyl, each        substituted or unsubstituted.

In a further embodiment, PLK inhibitors of the present inventioncomprise:

-   -   and the pharmaceutically acceptable salts thereof, wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₇ and the nitrogen to which L is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₃₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,

or any two R₅, R₆, R₉ and R₁₀ and are taken together to form asubstituted or unsubstituted ring. Particular examples of compoundsaccording to the present invention include, but are not limited to:

-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic    acid;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-cyclopropyl-3-methoxybenzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide;-   (R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   (S)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-1-yl)benzamide;-   N-(Azepan-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazepan-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2-(methylamino)-2-oxoethyl)piperidin-4-yl)benzamide;-   9-cyclopentyl-2-(4-(2-(dimethylamino)ethoxy)phenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   6-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one;-   9-cyclopentyl-7,7-difluoro-5-methyl-2-(2-oxoindolin-6-ylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   2-(1H-Indol-5-ylamino)-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-Cyclopentyl-7,7-difluoro-5-methyl-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-ylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide;-   3-Chloro-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethoxy)-benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic    acid;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic    acid;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   4-(9-Cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpyrrolidin-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methoxybenzamide;-   (1R,4R)-4-(4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)cyclohexyl    dihydrogen phosphate;-   N-(azepan-4-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((cis)-2-hydroxycyclohexyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-2-hydroxycyclohexyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-cyclopentylpiperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-(dimethylamino)ethyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-(dimethylamino)propyl)-3-methoxybenzamide;-   N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;-   9-cyclohexyl-7,7-difluoro-2-(2-methoxy-4-(4-methylpiperazine-1-carbonyl)-phenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-(dimethylamino)propyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methylbenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N′,N′-dimethylbenzohydrazide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-1-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-morpholinobenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-1-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide;-   N-(1-acetylazetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-3-yl)benzamide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-3-yl)benzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-3-yl)benzamide;-   (R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-cyclopropyl-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-ethylpiperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-isopropylpiperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(cyclopropylmethyl)piperazin-1-yl)-3-methoxybenzamidemethoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)-3-methoxybenzamide;-   4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic    acid;-   4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (S)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-Cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic    acid;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N—((R)-piperidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (S)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;-   4-((R)-9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N—((R)-piperidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   (S)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   (R)-2-(4-(4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)    piperidin-1-yl)ethyl dihydrogen phosphate;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic    acid;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   N-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-3-methoxybenzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-methoxybenzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide;-   (R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(piperidin-3-yl)benzamide;-   9-Cyclopentyl-7,7-difluoro-2-(5-fluoro-2-methoxyphenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoic    acid;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoic    acid;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropylazetidin-3-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-3-methoxybenzamide;-   N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropylazetidin-3-yl)-3-methoxybenzamide;-   N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-2-fluoro-5-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-isopropylazetidin-3-yl)-5-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentylazetidin-3-yl)-2-fluoro-5-methoxybenzamide;-   9-cyclopentyl-2-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-2-methoxyphenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-5-fluoro-2-methoxyphenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(2,2-difluorobenzo[d][1,3]dioxol-4-ylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-(dimethylamino)ethyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxyethyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-ethyl-3-methoxybenzamide-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-(dimethylamino)propyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methylbenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N′,N′-dimethylbenzohydrazide;-   (S)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide;-   (R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1S,2S)-2-hydroxycyclohexyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1S,2RS)-2-hydroxycyclohexyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-1-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-morpholinobenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-oxoazepan-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropylpiperidin-4-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)benzamide;-   N-(1-acetylpiperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-cyclopentylpiperazin-1-yl)-3-methoxybenzamide;-   (S)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide;    and-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide.

In addition, particular examples of compounds according to the presentinvention include, but are not limited to:

-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1S,2RS)-2-hydroxycyclohexyl)-3-methoxybenzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   (S)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide;-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;-   4-(9-Cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide-   N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide;-   (S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-3-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-ethylpiperazin-1-yl)-3-methoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(cyclopropylmethyl)piperazin-1-yl)-3-methoxybenzamidemethoxybenzamide;-   4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)-3-methoxybenzamide;-   4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide;    and-   4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide.

Particular examples of compounds according to the present invention alsoinclude, but are not limited to:

-   (R)-4-(9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (R)-4-(9-cyclohexyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (R)-4-(9-cyclobutyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide;-   4-((R)-9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N—((R)-piperidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide;-   4-((R)-9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N—((R)-quinuclidin-3-yl)benzamide;-   (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-(prop-1-ynyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (S)-4-(9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (S)-4-(9-cyclohexyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   (S)-4-(9-cyclobutyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;    and-   N-(azepan-4-yl)-4-((R)-9-cyclopentyl-7-ethynyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide.

Further, particular examples of compounds according to the presentinvention include, but are not limited to:

-   4-(5-cyclopentyl-7,7-difluoro-6,7-dihydro-5H-imidazo[1,2-d]pyrimido[4,5-b][1,4]diazepin-3-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(5-cyclopentyl-7-fluoro-7-methyl-6,7-dihydro-5H-imidazo[1,2-d]pyrimido[4,5-b][1,4]diazepin-3-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4,4-difluoro-5,6-dihydro-4H-pyrimido[4,5-b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4-fluoro-4-methyl-5,6-dihydro-4H-pyrimido[4,5-b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4,4-difluoro-5,6-dihydro-4H-pyrimido[4,5-b][1,2,4]triazolo[1,5-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4-fluoro-4-methyl-5,6-dihydro-4H-pyrimido[4,5-b][1,2,4]triazolo[1,5-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4,4-difluoro-5,6-dihydro-4H-pyrimido[4,5-b]tetrazolo[1,5-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-cyclopentyl-4-fluoro-4-methyl-5,6-dihydro-4H-pyrimido[4,5-b]tetrazolo[1,5-d][1,4]diazepin-8-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-6-(hydroxyimino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-6-(hydroxyimino)-5,7-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-(cyanoimino)-9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(6-(cyanoimino)-9-cyclopentyl-7-fluoro-5,7-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-6-(methoxyimino)-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7-fluoro-6-(methoxyimino)-5,7-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-(nitroimino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide;    and-   4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-(nitroimino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide.

In addition, particular examples of compounds according to the presentinvention include, but are not limited to:

-   (4-(9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxyphenyl)methanol;    and-   4-(9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide.

Still further, particular examples of compounds according to the presentinvention include, but are not limited to:

-   3-(cyclopentyl(2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-5-(methylamino)pyrimidin-4-yl)amino)-2,2-difluoropropanoic    acid; and-   3-(cyclopentyl(2-(5-fluoro-2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-5-(methylamino)pyrimidin-4-yl)amino)-2,2-difluoropropanoic    acid.

In another of its aspects, the present invention relates to methods ofmaking compounds that are useful as PLK inhibitors. In one embodiment,the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

reacting the first reaction product with a compound having the formulaR₂—Z₃under conditions that form a second reaction product having the formula

and

reacting the second reaction product with a compound having the formulaR₇-L-NR₃Hunder conditions that form a third reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₇ and the nitrogen to which L is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   or any two R₅, R₆, R₉ and R₁₀ and are taken together to form a        substituted or unsubstituted ring; and    -   Z₁, Z₂ and Z₃ are each independently a leaving group.

In another embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

reacting the second reaction product with a compound having the formulaR₂—Z₃under conditions that form a third reaction product having the formula

and

reacting the third reaction product with a compound having the formula

under conditions that form a fourth reaction product having the formula

-   -   wherein    -   X is selected from the group consisting of NR₁₄, O and S;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   Z₁ and Z₃ are each independently a leaving group.

In still another embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

reacting the third reaction product with a compound having the formula

under conditions that form a fourth reaction product having the formula

treating the fourth reaction product under conditions that form a fifthreaction product having the formula

reacting the fifth reaction product with a compound having the formula

under conditions that form a sixth reaction product having the formula

reacting the sixth reaction product with a compound having the formulaR₂—Z₃under conditions that form a seventh reaction product having the formula

and

reacting the seventh reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form an eighth reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxyl; and    -   Z₃ is a leaving group.

In yet another embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

reacting the second reaction product with a compound having the formula

under conditions that form a third reaction product having the formula

and

reacting the third reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form a fourth reaction product having the formula

-   -   wherein    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted,    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In a further embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

treating the third reaction product under conditions that form a fourthreaction product having the formula

treating the fourth reaction product under conditions that form a fifthreaction product having the formula

reacting the fifth reaction product with a compound having the formula

under conditions that form a sixth reaction product having the formula

and

reacting the sixth reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form a seventh reaction product having the formula

-   -   wherein    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In still a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

and

reacting the second reaction product with a compound having the formulaR₃₀—Brunder conditions that form a third reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₃ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   m is selected from the group consisting of 1, 2, 3, 4 and 5 (it        being understood that m−1 is m as defined minus 1);    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring; and    -   R₃₀ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₃₀ is a substituent        convertible in vivo into hydroxy, or R₂₉ and R₃₀ are taken        together to form a substituted or unsubstituted ring.

In yet a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formulaR₅—Z₄under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

reacting the third reaction product with a compound having the formula

under conditions that form a fourth reaction product having the formula

treating the fourth reaction product under conditions that form a fifthreaction product having the formula

reacting the fifth reaction product with a compound having the formulaR₂—Z₅under conditions that form a sixth reaction product having the formula

reacting the sixth reaction product with a compound having the formula

under conditions that form a seventh reaction product having the formula

and

reacting the seventh reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form a eighth reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxyl; and    -   Z₄ and Z₅ are each independently a leaving group.

In another embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

reacting the third reaction product with a compound having the formulaR₆—NH₂under conditions that form a fourth reaction product having the formula

treating the fourth reaction product under conditions that form a fifthreaction product having the formula

treating the fifth reaction product under conditions that form a sixthreaction product having the formula

treating the sixth reaction product under conditions that form a seventhreaction product having the formula

reacting the seventh reaction product with a compound having the formula

under conditions that form an eighth reaction product having the formula

treating the eighth reaction product under conditions that form a ninthreaction product having the formula

reacting the ninth reaction product with a compound having the formulaR₂—Z₅under conditions that form a tenth reaction product having the formula

reacting the tenth reaction product with a compound having the formula

under conditions that form an eleventh reaction product having theformula

and

reacting the eleventh reaction product with a compound having theformulaNHR₁₉R₂₀under conditions that form a twelfth reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxyl; and    -   Z₅ is a leaving group.

In still another embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

reacting the third reaction product with a compound having the formula

under conditions that form a fourth reaction product having the formula

and

reacting the fourth reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form a fifth reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxy.

In yet another embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

reacting the second reaction product with a compound having the formula

under conditions that form a third reaction product having the formula

treating the third reaction product under conditions that form a fourthreaction product having the formula

reacting the fourth reaction product with a compound having the formulaR₂—Z₅under conditions that form a fifth reaction product having the formula

treating the fifth reaction product under conditions that form a sixthreaction product having the formula

treating the sixth reaction product under conditions that form a seventhreaction product having the formula

treating the seventh reaction product under conditions that form aneighth reaction product having the formula

reacting the eighth reaction product with a compound having the formula

under conditions that form a ninth reaction product having the formula

and

reacting the ninth reaction product with a compound having the formulaNHR₁₉R₂₀under conditions that form a tenth reaction product having the formula

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   m is selected from the group consisting of 2, 3, 4 and 5;    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring;    -   R_(17a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl, amido,        amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido,        imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₉ are R₂₀ are each independently selected from the group        consisting of hydrogen, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring, or R₁₉ is a        substituent convertible in vivo into hydroxyl; and    -   Z₅ is a leaving group.

In a further embodiment, the methods comprise the steps of:

treating a compound having the formula

under conditions that form a first reaction product having the formula

reacting the first reaction product with a compound having the formula

under conditions that form a second reaction product having the formula

treating the second reaction product under conditions that form a thirdreaction product having the formula

and

reacting the third reaction product with a compound having the formula

under conditions that form a fourth reaction product having the formula

-   -   wherein    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the ring and the nitrogen to which L is        attached, wherein the atoms of the linker providing the        separation are selected from the group consisting of carbon,        oxygen, nitrogen, and sulfur;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, carbonyloxy,        oxycarbonyl, amido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In still another of its aspects, the present invention relates tointermediates that are useful in making PLK inhibitors. In oneembodiment, the intermediates comprise

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   Z₂ is a leaving group.

In another embodiment, the intermediates comprise

-   -   wherein    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   Z₁ is a leaving group.

In still another embodiment, the intermediates comprise

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group.

In yet another embodiment, the intermediates comprise

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, the intermediates comprise

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₅ and R₁₆ are each independently selected from the group        consisting of hydrogen, cyano, carbonyl, oxycarbonyl, amido,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₄ and R₁₅ are taken together        with the atom to which they are bound to form a carbonyl or        imino group.

In still a further embodiment, the intermediates comprise

-   -   wherein    -   W is selected from the group consisting of CR₈ and N;    -   X is selected from the group consisting of NR₁₄, O and S;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₂ and R₁ or R₁₄ are taken        together to form a substituted or unsubstituted ring;    -   R₄ is halo;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₄ is selected from the group consisting of (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, the intermediates comprise

-   -   wherein    -   Y is —(CR₉R₁₀)_(n)—;    -   n is selected from the group consisting of 1, 2, 3 and 4;    -   R₁ is selected from the group consisting of hydrogen, cyano,        thio, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₄ is halo;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₆ is selected from the group consisting of hydrogen, carbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₉ and R₁₀ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₉ and R₁₀ are taken together        with the carbon to which they are attached to form C═O, C═S,        C═NR₁₁ or C═CR₁₂R₁₃;    -   R₁₁ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₂ and R₁₃ are each independently selected from the group        consisting of hydrogen, halo, nitro, cyano, oxycarbonyl, amido,        amino (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In one variation of each of the above embodiments, W is N

In another variation of each of the above embodiments and variations, Xis O.

In still another variation of each of the above embodiments andvariations, L is a substituted or unsubstituted (C₁₋₃)alkyl. In afurther variation of each of the above embodiments and variations, L isabsent.

In yet another variation of each of the above embodiments andvariations, L is —CHR₂₃—; and R₂₃ is selected from the group consistingof hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₁ is hydrogen.

In still a further variation of each of the above embodiments andvariations, R₂ is selected from the group consisting of hydrogen and asubstituted or unsubstituted (C₁₋₃)alkyl. In yet a further variation ofeach of the above embodiments and variations, R₂ is methyl.

In another variation of each of the above embodiments and variations, R₃is hydrogen. In still another variation of each of the above embodimentsand variations, R₃ is a substituent convertible in vivo to hydrogen. Inyet another variation of each of the above embodiments and variations,R₃ is selected from the group consisting of hydrolyzable groups, groupshaving an oxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, arylsulfonyl groups, methyl groups substituted withphenyl or benzyloxy, arylmethoxycarbonyl groups, andhalogenoethoxycarbonyl groups.

In a further variation of each of the above embodiments and variations,R₄ is fluoro. In still a further variation of each of the aboveembodiments and variations, R₄ is bromo.

In yet a further variation of each of the above embodiments andvariations, R₅ is selected from the group consisting of hydrogen, halo,a substituted or unsubstituted (C₁₋₃)alkyl and a substituted orunsubstituted (C₁₋₃)alkenyl. In another variation of each of the aboveembodiments and variations, R₅ is a substituted or unsubstituted(C₁₋₃)alkenyl. In still another variation of each of the aboveembodiments and variations, R₅ is halo. In yet another variation of eachof the above embodiments and variations, wherein R₅ is fluoro. In afurther variation of each of the above embodiments and variations,wherein R₅ is bromo.

In still a further variation of each of the above embodiments andvariations, R₆ is selected from the group consisting of (C₁₋₅)alkyl and(C₃₋₁₂)cycloalkyl, each substituted or unsubstituted. In yet a furthervariation of each of the above embodiments and variations, R₆ isselected from the group consisting of isopropyl, cyclopropyl,cyclopentyl and cyclohexyl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variations,

-   -   R₆ is selected from the group consisting of (C₁₋₅)alkyl and        -L₁-R₂₄;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₄ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur; and    -   R₂₄ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₇ is a substituted or unsubstituted hetero(C₁₋₁₀)aryl.

In a further variation of each of the above embodiments and variations,R₇ is

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₇ is independently selected from the group consisting of        halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy,        aryloxy, heteroaryloxy, carbamoyloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino,        ureido, imino, sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₇ are taken together to        form a substituted or unsubstituted ring.

In still a further variation of each of the above embodiments andvariations, R₇ is

-   -   wherein    -   R_(17a), R_(17b) and R_(17c), are each independently selected        from the group consisting of hydrogen, halo, nitro, cyano, thio,        oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy,        carbamoyloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, carboxyamino, ureido, imino,        sulfonyl, aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₈ is selected from the group consisting of hydrogen and asubstituted or unsubstituted (C₁₋₅)alkyl.

In a further variation of each of the above embodiments and variations,R₁₅ is hydrogen. In still a further variation of each of the aboveembodiments and variations, R₁₅ is a substituted or unsubstituted(C₁₋₃)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₁₆ is hydrogen. In another variation of each of the aboveembodiments and variations, R₁₆ is a substituted or unsubstituted(C₁₋₁₃)alkyl.

In still another variation of each of the above embodiments andvariations, at least one R₁₇ is a substituted or unsubstituted alkoxy.In yet another variation of each of the above embodiments andvariations, at least one R₁₇ is methoxy. In a further variation of eachof the above embodiments and variations, at least one R₁₇ is a halo. Instill a further variation of each of the above embodiments andvariations, at least one R₁₇ is fluoro.

In yet another variation of each of the above embodiments andvariations, at least one R₁₇ comprises —C(O)NR₂₅R₂₆, wherein R₂₅ and R₂₆are each independently selected from the group consisting of hydrogen,oxy, hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₂₅ andR₂₆ are taken together to form a substituted or unsubstituted ring.

In a further variation of each of the above embodiments and variations,at least one R₁₇ comprises —C(O)OR₂₇, wherein R₂₇ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations, m is 2.

In yet a further variation of each of the above embodiments andvariations, R_(17a) is selected from the group consisting of hydrogen,halo, alkoxy and (C₁₋₁₀)alkyl, each substituted or unsubstituted. Inanother variation of each of the above embodiments and variations,R_(17a) is a substituted or unsubstituted alkoxy. In still anothervariation of each of the above embodiments and variations, R_(17a) ismethoxy.

In yet another variation of each of the above embodiments andvariations, R_(17b) comprises —C(O)NR₂₅R₂₆, wherein R₂₅ and R₂₆ are eachindependently selected from the group consisting of hydrogen, oxy,hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₂₅ andR₂₆ are taken together to form a substituted or unsubstituted ring.

In a further variation of each of the above embodiments and variations,R_(17b) comprises —C(O)OR₂₇, wherein R₂₇ is selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variations, atleast one R_(17c) is a halo. In still another variation of each of theabove embodiments and variations, at least one R_(17c) is fluoro.

In still a further variation of each of the above embodiments andvariations, R₁₈ is hydroxy.

In yet a further variation of each of the above embodiments andvariations, R₁₉ is hydrogen. In another variation of each of the aboveembodiments and variations, R₁₉ is a phosphate.

In still another variation of each of the above embodiments andvariations, R₂₀ is selected from the group consisting of hydrogen, halo,amino, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₁₋₁₀)azaalkyl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations,

-   -   R₂₀ is selected from the group consisting of (C₁₋₅)alkyl and        -L₂-R₂₈;    -   L₂ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₂₈ and the ring to which L₂ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur; and    -   R₂₈ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,

-   -   R₂₀ is selected from the group consisting of

-   -   q is selected from the group consisting of 0, 1, 2, 3, 4 and 5;    -   R₂₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₂₉ are taken together to        form a substituted or unsubstituted ring, or R₂₉ is a        substituent convertible in vivo into hydroxy; and    -   R₃₀ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₃₀ is a substituent        convertible in vivo into hydroxy, or R₂₉ and R₃₀ are taken        together to form a substituted or unsubstituted ring.

In still a further variation of each of the above embodiments andvariations, R₁₅ and R₂₁ are taken together to form a substituted orunsubstituted 5-, 6-, 7- or 8-membered ring. In yet a further variationof each of the above embodiments and variations, R₁₅ and R₂₁ are takentogether to form a substituted or unsubstituted pyrrolidine. In anothervariation of each of the above embodiments and variations, the ringformed by R₁₅ and R₂₁ is substituted with one or more substituentsindependently selected from the group consisting of hydrogen, halo,nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,heteroaryloxy, carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₂₇ is hydroxy.

In yet another variation of each of the above embodiments andvariations, R₃₁ is hydroxy.

In a further variation of each of the above embodiments and variations,R₃₂ is selected from the group consisting of hydrogen and (C₁₋₃)alkyl.In still a further variation of each of the above embodiments andvariations, R₃₂ is hydrogen.

In yet a further variation of each of the above embodiments andvariations, R₃₃ is selected from the group consisting of hydrogen and(C₁₋₃)alkyl. In another variation of each of the above embodiments andvariations, R₃₃ is hydrogen.

In yet another variation of each of the above embodiments andvariations, Z₁ is halo. In a further variation of each of the aboveembodiments and variations, Z₂ is halo. In still a further variation ofeach of the above embodiments and variations, Z₃ is halo. In yet afurther variation of each of the above embodiments and variations, Z₄ ishalo. In another variation of each of the above embodiments andvariations, Z₅ is halo. In yet another variation of each of the aboveembodiments and variations, R₇ is an optionally substituted 3-fluoro or3-chloro-1,4-phenylene. In yet another variation of each of the aboveembodiments, R₇ is a 3-fluoro or 3-chloro-1,4-phenylene optionallysubstituted with from 1 to 3 groups independently selected from thegroup consisting of halo, nitro, cyano, optionally substituted(C₁₋₄)alkoxy, and optionally substituted (C₁₋₄)alkyl.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas a hydrogen.

It is further noted that the compound may be present in a mixture ofstereoisomers, or the compound may comprise a single stereoisomer.

The present invention also relates to the use of a compound according toany one of above embodiments and variations as a medicament.

In addition, the present invention relates to the use of a compoundaccording to any one of the above embodiments and variations in themanufacture of a medicament for inhibiting a polo-like kinase.

Further, the present invention relates to the use of a compoundaccording to any one of the above embodiments and variations in themanufacture of a medicament for treating a disease state for which apolo-like kinase possess activity that contributes to the pathologyand/or symptomology of the disease state.

The present invention also relates to the use of a compound according toany one of the above embodiments and variations in the manufacture of amedicament for treating hyperproliferative disorders; cancer;inflammatory diseases; auto-immune diseases; chemotherapy agent-inducedalopecia and mucositis; cardiovascular diseases; viral, bacterial,fungal and/or parasitic infectious diseases; nephrological diseases;chronic and acute neurodegenerative diseases; skin diseases; bonediseases; and the protection of proliferating cells.

The present invention also provides a pharmaceutical compositioncomprising as an active ingredient a compound according to any one ofthe above embodiments and variations. In one particular variation, thecomposition is a solid formulation adapted for oral administration. Inanother particular variation, the composition is a liquid formulationadapted for oral administration. In yet another particular variation,the composition is a tablet. In still another particular variation, thecomposition is a liquid formulation adapted for parenteraladministration.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising a compound according to any one of the aboveembodiments and variations, wherein the composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibiting akinase comprising contacting the kinase with a compound of any one ofthe above embodiments and variations.

In yet another of its aspects, there is provided a method of inhibitinga kinase comprising causing a compound of any one of the aboveembodiments and variations to be present in a subject in order toinhibit the kinase in vivo.

In a further of its aspects, there is provided a method of inhibiting akinase comprising administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits the kinase in vivo, the second compound being a compoundaccording to any one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which a kinase possesses activity that contributes tothe pathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which a kinase possesses activity that contributes tothe pathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which a kinase possesses activity that contributes tothe pathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits thekinase in vivo, the second compound being a compound according to anyone of the above embodiments and variations.

In one variation of each of the above methods the disease state isselected from the group consisting of hyperproliferative disorders;cancer (e.g., solid tumors, leukemias, lymphomas, non-small cell lungcancers and esophageal carcinomas); inflammatory and autoimmune diseases(e.g., psoriasis, alopecia; multiple sclerosis; colitis, arthritis,Alzheimer's disease, glomerulonephritis and wound healing); chemotherapyagent-induced alopecia and mucositis; cardiovascular diseases (e.g.,stenoses, arterioscleroses, restenoses, and hypertrophy); viral,bacterial, fungal and/or parasitic infectious diseases (e.g.,cytomegalic infections, herpes, hepatitis B and C, Karposi's sarcoma,HIV diseases); nephrological diseases (e.g., glomerulonephritis);chronic and acute neurodegenerative diseases (e.g., Huntington'sdisease, amyotrophic lateral sclerosis, Parkinson's disease, AIDSdementia, Alzheimer's disease, ischemias of the brain and neurotraumas);skin diseases (e.g., psoriasis); bone diseases; the protection ofproliferating cells (e.g., hair, intestinal, blood and progenitor cells)from DNA damage caused by radiation, UV treatment and/or cytostatictreatment.

In another variation of each of the above methods, the kinase is aprotein tyrosine kinase. In still another variation of each of the abovemethods, the kinase is a Polo-like Kinase (PLK). In yet anothervariation, the PLK is PLK1, PLK2, PLK3, PLK4, TTK, FAK and/or AIK

Salts, Hydrates, and Prodrugs of Kinase Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptonate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamoylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Compositions Comprising Kinase Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The kinase inhibitors and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a kinase inhibitor, in the course of a coordinated treatment toachieve an improved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyvinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of an inhibitor of thepresent invention to reduce kinase activity in vivo, thereby treatingthe disease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more kinase inhibitors, optionally 0.1-95%,and optionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose, and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol, and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof, and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurate,and polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions include EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is known and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the kinase inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The kinase inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a kinase inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The kinase inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the kinase inhibitor alone or in combination withother pharmaceutically acceptable excipients can also be administered.

Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention 1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica 1%.Kits Comprising Kinase Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with kinases. It is noted that diseasesare intended to cover all conditions for which the kinase possessesactivity that contributes to the pathology and/or symptomology of thecondition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas PLK inhibitors for a variety of subjects (e.g., humans, non-humanmammals and non-mammals). The optimal dose may vary depending upon suchconditions as, for example, the type of subject, the body weight of thesubject, the route of administration, and specific properties of theparticular compound being used. In general, the daily dose for oraladministration to an adult (body weight of about 60 kg) is about 1 to1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Combination Therapies

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with kinase inhibitors according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: 1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; 2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or 3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. For example, such other therapeutic agents mayadditively or synergistically combine with the kinase inhibitors toinhibit undesirable cell growth, such as inappropriate cell growthresulting in undesirable benign conditions or tumor growth.

In one embodiment, a method is provided for treating a cellproliferative disease state comprising treating cells with a compoundaccording to the present invention in combination with ananti-proliferative agent, wherein the cells are treated with thecompound according to the present invention before, at the same time,and/or after the cells are treated with the anti-proliferative agent,referred to herein as combination therapy. It is noted that treatment ofone agent before another is referred to herein as sequential therapy,even if the agents are also administered together. It is noted thatcombination therapy is intended to cover when agents are administeredbefore or after each other (sequential therapy) as well as when theagents are administered at the same time.

Examples of therapeutic agents that may be used in combination withkinase inhibitors include, but are not limited to, anticancer agents,alkylating agents, antibiotic agents, antimetabolic agents, hormonalagents, plant-derived agents, and biologic agents.

Alkylating agents are polyfunctional compounds that have the ability tosubstitute alkyl groups for hydrogen ions. Examples of alkylating agentsinclude, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). These compounds react with phosphate, amino, hydroxyl,sulfihydryl, carboxyl, and imidazole groups. Under physiologicalconditions, these drugs ionize and produce positively charged ion thatattach to susceptible nucleic acids and proteins, leading to cell cyclearrest and/or cell death. Combination therapy including a kinaseinhibitor and an alkylating agent may have therapeutic synergisticeffects on cancer and reduce sides affects associated with thesechemotherapeutic agents.

Antibiotic agents are a group of drugs that produced in a manner similarto antibiotics as a modification of natural products. Examples ofantibiotic agents include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interferes with cell growth by targeting different cellularcomponents. For example, anthracyclines are generally believed tointerfere with the action of DNA topoisomerase II in the regions oftranscriptionally active DNA, which leads to DNA strand scissions.Bleomycin is generally believed to chelate iron and forms an activatedcomplex, which then binds to bases of DNA, causing strand scissions andcell death. Combination therapy including a kinase inhibitor and anantibiotic agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Antimetabolic agents are a group of drugs that interfere with metabolicprocesses vital to the physiology and proliferation of cancer cells.Actively proliferating cancer cells require continuous synthesis oflarge quantities of nucleic acids, proteins, lipids, and other vitalcellular constituents. Many of the antimetabolites inhibit the synthesisof purine or pyrimidine nucleosides or inhibit the enzymes of DNAreplication. Some antimetabolites also interfere with the synthesis ofribonucleosides and RNA and/or amino acid metabolism and proteinsynthesis as well. By interfering with the synthesis of vital cellularconstituents, antimetabolites can delay or arrest the growth of cancercells. Examples of antimetabolic agents include, but are not limited to,fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin,hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine,pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase,and gemcitabine. Combination therapy including a kinase inhibitor and aantimetabolic agent may have therapeutic synergistic effects on cancerand reduce sides affects associated with these chemotherapeutic agents.

Hormonal agents are a group of drug that regulate the growth anddevelopment of their target organs. Most of the hormonal agents are sexsteroids and their derivatives and analogs thereof, such as estrogens,androgens, and progestins. These hormonal agents may serve asantagonists of receptors for the sex steroids to down regulate receptorexpression and transcription of vital genes. Examples of such hormonalagents are synthetic estrogens (e.g. diethylstibestrol), antiestrogens(e.g. tamoxifen, toremifene, fluoxymesterol and raloxifene),antiandrogens (bicalutamide, nilutamide, flutamide), aromataseinhibitors (e.g., aminoglutethimide, anastrozole and tetrazole),ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone. Combination therapy including a kinase inhibitor and ahormonal agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Plant-derived agents are a group of drugs that are derived from plantsor modified based on the molecular structure of the agents. Examples ofplant-derived agents include, but are not limited to, vinca alkaloids(e.g., vincristine, vinblastine, vindesine, vinzolidine andvinorelbine), podophyllotoxins (e.g., etoposide (VP-16) and teniposide(VM-26)), taxanes (e.g., paclitaxel and docetaxel). These plant-derivedagents generally act as antimitotic agents that bind to tubulin andinhibit mitosis. Podophyllotoxins such as etoposide are believed tointerfere with DNA synthesis by interacting with topoisomerase II,leading to DNA strand scission. Combination therapy including a kinaseinhibitor and a plant-derived agent may have therapeutic synergisticeffects on cancer and reduce sides affects associated with thesechemotherapeutic agents.

Biologic agents are a group of biomolecules that elicit cancer/tumorregression when used alone or in combination with chemotherapy and/orradiotherapy. Examples of biologic agents include, but are not limitedto, immuno-modulating proteins such as cytokines, monoclonal antibodiesagainst tumor antigens, tumor suppressor genes, and cancer vaccines.Combination therapy including a kinase inhibitor and a biologic agentmay have therapeutic synergistic effects on cancer, enhance thepatient's immune responses to tumorigenic signals, and reduce potentialsides affects associated with this chemotherapeutic agent.

Cytokines possess profound immunomodulatory activity. Some cytokinessuch as interleukin-2 (IL-2, aldesleukin) and interferon havedemonstrated antitumor activity and have been approved for the treatmentof patients with metastatic renal cell carcinoma and metastaticmalignant melanoma. IL-2 is a T-cell growth factor that is central toT-cell-mediated immune responses. The selective antitumor effects ofIL-2 on some patients are believed to be the result of a cell-mediatedimmune response that discriminate between self and nonself. Examples ofinterleukins that may be used in conjunction with a kinase inhibitorinclude, but are not limited to, interleukin 2 (IL-2), and interleukin 4(IL-4), interleukin 12 (IL-12).

Interferon include more than 23 related subtypes with overlappingactivities, all of the IFN subtypes within the scope of the presentinvention. IFN has demonstrated activity against many solid andhematologic malignancies, the later appearing to be particularlysensitive.

Other cytokines that may be used in conjunction with a kinase inhibitorinclude those cytokines that exert profound effects on hematopoiesis andimmune functions. Examples of such cytokines include, but are notlimited to erythropoietin, granulocyte-CSF (filgrastin), andgranulocyte, macrophage-CSF (sargramostim). These cytokines may be usedin conjunction with a kinase inhibitor to reduce chemotherapy-inducedmyelopoietic toxicity.

Other immuno-modulating agents other than cytokines may also be used inconjunction with a kinase inhibitor to inhibit abnormal cell growth.Examples of such immuno-modulating agents include, but are not limitedto bacillus Calmette-Guerin, levamisole, and octreotide, a long-actingoctapeptide that mimics the effects of the naturally occurring hormonesomatostatin.

Monoclonal antibodies against tumor antigens are antibodies elicitedagainst antigens expressed by tumors, preferably tumor-specificantigens. For example, monoclonal antibody HERCEPTIN® (Trastruzumab) israised against human epidermal growth factor receptor2 (HER2) that isoverexpressed in some breast tumors including metastatic breast cancer.Overexpression of HER2 protein is associated with more aggressivedisease and poorer prognosis in the clinic. HERCEPTIN® is used as asingle agent for the treatment of patients with metastatic breast cancerwhose tumors over express the HER2 protein. Combination therapyincluding a kinase inhibitor and HERCEPTIN® may have therapeuticsynergistic effects on tumors, especially on metastatic cancers.

Another example of monoclonal antibodies against tumor antigens isRITUXAN® (Rituximab) that is raised against CD20 on lymphoma cells andselectively deplete normal and malignant CD20⁺ pre-B and mature B cells.RITUXAN® is used as single agent for the treatment of patients withrelapsed or refractory low-grade or follicular, CD20+, B cellnon-Hodgkin's lymphoma. Combination therapy including a kinase inhibitorand RITUXAN® may have therapeutic synergistic effects not only onlymphoma, but also on other forms or types of malignant tumors.

Tumor suppressor genes are genes that function to inhibit the cellgrowth and division cycles, thus preventing the development ofneoplasia. Mutations in tumor suppressor genes cause the cell to ignoreone or more of the components of the network of inhibitory signals,overcoming the cell cycle check points and resulting in a higher rate ofcontrolled cell growth-cancer. Examples of the tumor suppressor genesinclude, but are not limited to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1and BRCA2.

DPC-4 is involved in pancreatic cancer and participates in a cytoplasmicpathway that inhibits cell division. NF-1 codes for a protein thatinhibits Ras, a cytoplasmic inhibitory protein. NF-1 is involved inneurofibroma and pheochromocytomas of the nervous system and myeloidleukemia. NF-2 encodes a nuclear protein that is involved in meningioma,schwanoma, and ependymoma of the nervous system. RB codes for the pRBprotein, a nuclear protein that is a major inhibitor of cell cycle. RBis involved in retinoblastoma as well as bone, bladder, small cell lungand breast cancer. P53 codes for p53 protein that regulates celldivision and can induce apoptosis. Mutation and/or inaction of p53 isfound in a wide ranges of cancers. WT1 is involved in Wilms tumor of thekidneys. BRCA1 is involved in breast and ovarian cancer, and BRCA2 isinvolved in breast cancer. The tumor suppressor gene can be transferredinto the tumor cells where it exerts its tumor suppressing functions.Combination therapy including a kinase inhibitor and a tumor suppressormay have therapeutic synergistic effects on patients suffering fromvarious forms of cancers.

Cancer vaccines are a group of agents that induce the body's specificimmune response to tumors. Most of cancer vaccines under research anddevelopment and clinical trials are tumor-associated antigens (TAAs).TAA are structures (i.e. proteins, enzymes or carbohydrates) which arepresent on tumor cells and relatively absent or diminished on normalcells. By virtue of being fairly unique to the tumor cell, TAAs providetargets for the immune system to recognize and cause their destruction.Example of TAAs include, but are not limited to gangliosides (GM2),prostate specific antigen (PSA), alpha-fetoprotein (AFP),carcinoembryonic antigen (CEA) (produced by colon cancers and otheradenocarcinomas, e.g. breast, lung, gastric, and pancreas cancers),melanoma associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),papillomavirus E6 and E7 fragments, whole cells or portions/lysates ofantologous tumor cells and allogeneic tumor cells.

An adjuvant may be used to augment the immune response to TAAs. Examplesof adjuvants include, but are not limited to, bacillus Calmette-Guerin(BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH),interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor(GM-CSF) and cytoxan, a chemotherapeutic agent which is believe toreduce tumor-induced suppression when given in low doses.

EXAMPLES Preparation of Kinase Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine SerumAlbumin) CBZ (benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid chromatography) Hz(Hertz) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)RT (ambient temperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

General synthetic routes for producing compounds of the presentinvention are shown in the following schemes.

Referring to Scheme 1, Compound C is obtained by reductive amination ofCompound 1B by Compound 1A using, for example, sodiumtriacetoxyborohydride or sodium cyanoborohydride. In particularembodiments, Z₁ is Me or Et; R₆ is cyclopentyl, isopropyl or a 2-6membered alkyl bridge to R₂ or R₃ of Y; and R₂ and R₃ of Y are eachindependently H, Me, Et or a 2-6 membered alkyl bridge. In otherparticular embodiments, Compound 1B is cyclopentanone, cyclohexanone orketone.

Referring to Scheme 2, Compound C is prepared by Michael addition ofCompound 2A (i.e., ethyl acrylate) with Compound 2B (i.e.,cyclopropylamine or cyclopentylamine) followed by alkylation with R₅—Z₃.

Referring to Scheme 3, Compound 3A is converted to Compound C usingCompound 3B (i.e., cyclopropylamine or cyclopentylamine) in the presenceof base (i.e., K₂CO₃) and sodium iodide.

Referring to Scheme 4, Compound C is treated with Compound 4A in thepresence of base (i.e., K₂CO₃ or diisopropylethylamine) to give Compound4B. Compound 4B is transformed by reduction using reduced iron andsubsequent cyclization reaction to afford Compound 4C. Compound 4E isprepared by N-alkylation of Compound 4C with Compound 4D (e.g., alkylhalide (e.g., iodomethane)). Compound 4E is treated with Compound 4F inthe presence of a catalytic amount of acid (i.e., conc. HCl orpyridinium chloride) (about 0.1 to 10 equivalents) to obtain Compound4G. Compound 4F is one that either has R₇ as desired in the end productor gives rise to R₇ as desired in the end product.

Referring to Scheme 5, Compound C is treated with Compound 5A in thepresence of base (i.e., K₂CO₃ or diisopropylethylamine) to give Compound5B. Compound 5B is transformed by reduction using reduced iron andsubsequent cyclization reaction to afford Compound 5C. Compound 5E isprepared by N-alkylation of Compound 5C with alkyl halide 5D (i.e.,iodomethane). Compound 5E is treated with aniline or benzylamine(Compound 5F, L=CHR₁₄) in the presence of a catalytic amount of acid(i.e., conc. HCl or pyridinium chloride) to obtain Compound 5G.

Coupling reaction of Compound 6A with amine (Compound 6B, i.e.,methylamine or 1-methylpiperidin-4-amine) using appropriate couplingreagents (i.e., HATU, TBTU, etc.) is carried out to give Compound 6C.

Referring to Scheme 7, Compound 7A is treated with dibenzyl amine (7B)in ethanol to get 7C. Reformatsky reaction of ethyl α-bromo acetate (7D)with 7C in presence of Zinc dust, trimethyl silyl chloride to yieldCompound 7E, which is subjected to hydrogenation in the presence of apalladium catalyst (i.e., Pd(OH)₂ on Carbon) to yield 7F. Reductiveamination of Compound 7F with aldehyde or ketone (i.e., cyclopentanoneor cyclohexanone) in presence of sodium triacetoxy borohydride andsodium acetate to afford 7G. Compound 7G is subjected to SNAr reactionwith substituted pyrimidine 7H (i.e., 2,4-dichloro 5-nitro pyrimidine)in presence of base (i.e., K₂CO₃) to afford Compound 71, which onreductive cyclization using a metal/acid catalyst (i.e., Fe/HCl orSn/HCl) to obtain Compound 7J. Compound 7J is refluxed with Compound 7K(i.e., 4-amino 3-methoxy benzoic acid) in presence of an acid catalyst(i.e., conc.HCl or TsOH) to get Compound 7L, which is coupled with anamine (i.e., methylamine or 1-methylpiperidin-4-amine) to obtainCompound 7M.

Compound 7N is subjected to N-alkylation using an alkylating agent(i.e., methyl iodide) to afford Compound 7O. Compound 7O is refluxedwith Compound 7P (i.e., 4-amino-3-methoxy benzoic acid) in presence of aacid catalyst (i.e., conc.HCl or TsOH) to yield Compound 7Q, which issubjected to an amine (i.e., methylamine or 1-methylpiperidin-4-amine)using appropriate coupling reagents (i.e., HATU, TBTU etc.) to give theCompound 7R.

Referring to Scheme 8, Compound 8A is treated with a base (i.e., sodiummethoxide) in methanol to afford Compound 8B, which is hydrogenated inpresence of a catalyst (i.e., Pd/C) to yield Compound 8C. Compound 8D isrefluxed with Compound 8C in presence of acid catalyst (i.e., conc.HClor TsOH) to give Compound 8E. Compound 8E is condensed with an amine(i.e., methylamine or 1-methylpiperidin-4-amine) using appropriatecoupling reagents (i.e., HATU, TBTU etc.) to give the Compound 8F.

Referring to Scheme 9, Compound 9A is treated with an oxidation agent(e.g., sodium perborate in acetic acid) to afford Compound 9B, which isconverted to its methyl ether using a base (i.e., NaOMe) in methanol togive Compound 9C. Compound 9C is subjected to a nucleophilicsubstitution reaction in presence of CuCN to yield Compound 9D, which ishydrolyzed to its acid 9E in presence of strong acid (i.e., conc.HCl).Compound 9E is hydrogenated in presence of a catalyst (i.e., Pd/C) andacetic acid in alcohol such as methanol to yield Compound 9F. Compound9F is refluxed with Compound 9G in presence of acid catalyst (i.e.,conc.HCl or TsOH) to give Compound 9H. Compound 9H is treated with anamine (i.e., methylamine or 1-methylpiperidin-4-amine) using appropriatecoupling reagents (i.e., HATU, TBTU etc.) to give the Compound 9I.

Referring to Scheme 10, Compound 10A is coupled with a piperazinederivative (i.e., benzyl 4-aminopiperazine-1-carboxylate) usingappropriate coupling reagents (i.e., HATU, TBTU etc.) to give theCompound 10B. Compound 10B is subjected to hydrogenation for Cbz groupdeprotection in presence of a catalyst (i.e., Pd—C) in alcohol to getCompound 10C. Compound 10C is alkylated using an alkyl halide (i.e.,ethyl bromide or isopropyl bromide) in presence of a base such asdiisopropyl ethyl amide to yield Compound 10D.

Referring to Scheme 11, Compound 7M is subjected to O-alkylation usingan alkylating agent (i.e., methyl iodide) to afford Compound 11A.

Referring to Scheme 12, Compound 12A is alkylated with an alkylylatingagent (i.e., iodomethane) in presence of a strong base (i.e., 60% NaH inmineral oil) to get Compound 12B, which is reduced to its amine 12C bymeans of hydrogenation in presence of a catalyst (i.e., Rh—Al₂O₃) inbasic medium NH₃ in ethanol. Compound 12C is subjected to reductiveamination with an aldehyde or a ketone (i.e., cyclopentanone orcyclohexanone) in presence of sodium triacetoxy borohydride and sodiumacetate to afford 12D. Compound 12D is subjected to SNAr reaction with12E (i.e., 2,4-dichloro 5-nitro pyrimidine) in presence of a base (i.e.,K₂CO₃) to afford Compound 12F, which on reductive cyclization using ametal/acid catalyst in acetic acid (i.e., Fe/HCl or Sn/HCl) to obtainCompound 12G. Compound 12G is alkylated with an alkyl halide (i.e.,iodomethane) to obtain Compound 12H. Compound 12H is refluxed withCompound 121 in presence of an acid catalyst (i.e., conc.HCl or TsOH) inisopropanol to get Compound 12J, which is coupled with an amine (i.e.,methylamine or 1-methylpiperidin-4-amine) using appropriate couplingreagents (i.e., HATU, TBTU etc.) to give the Compound 12K.

Referring to Scheme 13, 13B can be prepared upon treatment of 13A withformaldehyde and dimethylamine under reflux condition. After conversionof 13B to the methylester 13C, the double bond is oxidized to an epoxide13D, which is transformed to amino alcohol 13E with alkylamine. Thehydroxyl group can be converted to a fluoride 13G after the secondary isprotected with a benzyl group. 13G is deprotected through catalytichydrogenation to 13H, which is further treat with 13I in the presence ofbase to give 13J. Upon reduction of the nitro group with a reducingagent under acidic heating condition, Compound 13K can be readilyobtained. Compound 13L is prepared by N-alkylation of Compound 13K withR₂—Z₄ (i.e., iodomethane). Compound 13L is treated with aniline orbenzylamine in the presence of a catalytic amount of acid (i.e., conc.HCl or pyridinium chloride) to obtain Compound 13N. Coupling reaction ofCompound 13N with amine (i.e., methylamine or 1-methylpiperidin-4-amine)using appropriate coupling reagents (i.e., HATU, TBTU etc.) is carriedout to give Compound 13O.

Referring to Scheme 14, Compound 14A is treated with acetaldehyde in thepresence of base (i.e. LDA) to give 14B. The hydroxyl group on 14B isthen mesylated at low temperature followed by base treatment (i.e. NaH)to yield the eliminated product Compound 14C. Under the coolingcondition, Compound 14C is further reacted with halogen source 14H(e.g., N-fluorobenzenesulfonamide) in the presence of base such as LDAto give vinyl fluoro compound 14D. Compound 14D is refluxed withCompound 14E in presence of an acid catalyst (i.e., conc.HCl or TsOH) inisopropanol to get Compound 14F, which is coupled with an amine (i.e.,methylamine or 1-methylpiperidin-4-amine) using appropriate couplingreagents (i.e., HATU, TBTU etc.) to give the Compound 14G.

Referring to Scheme 15, hydrogenation of compound 15A in presence of acatalyst (i.e., Rh—Al₂O₃ using basic medium such as NH₃/ethanol to givethe compound 15B. Reductive amination of compound 15B with aldehyde orketone (i.e., cyclopentanone or cyclohexanone) in presence of sodiumtriacetoxy borohydride to afford 15C. Compound 15C is subjected to SNArreaction with 15D (i.e., 2,4-dichloro 5-nitro pyrimidine) in presence ofa base (i.e., K₂CO₃) to afford compound 15E, which on reductivecyclization using a metal/acid catalyst in acetic acid (i.e., Fe/HCl orSn/HCl) to obtain compound 15F. Compound 15F is N-alkylated using a base(i.e., NaH or t-BuOK) and alkyl halide (i.e., iodomethane) in DMA toafford compound 15G. Compound 15G is reacted with oxalyl chloride inpresence of a base (i.e., BuLi) to yield the compound 15H, which isfurther reacted with CBr₄/PPh₃ to afford compound 15I. Compound 15I isreacted with a strong base (i.e., BuLi) to yield compound 15J. Compound15J is refluxed with compound 15K in presence of an acid catalyst (i.e.,conc.HCl or TsOH) to get compound 15L, which is coupled with an amine(i.e., methylamine or 1-methylpiperidin-4-amine) using appropriatecoupling reagents (i.e., HATU, TBTU etc.) to give the compound 15M.Final compound 15M is subjected to chiral separation to get the pureenantiomers.

Referring to Scheme 16, Compound 16A is treated with a thiolatingreagent to give Compound 16B. Compound 16B is transformed to amidineCompound 16D reaction with an ethanolic amine represented by 16C.Compound 16E is prepared by oxidation and cyclization of Compound 16D.Compound 16E is treated with aniline or benzylamine (Compound 16G) inthe presence of a catalytic amount of acid (i.e., conc. HCl orpyridinium chloride) to obtain Compound 16F.

Bicyclic compounds 17A can be subjected to a ring opening reaction inorder to form compounds 17B. In particular, exposing compound 17A to abase, such as NaOH, opens ring A to form compound 17B. Conversely,exposing compound 17B to an acid will form compound 17A. Accordingly, itwill be appreciated that compounds of the present invention can beformulated with a base, to force the equilibrium to the right, or withan acid, to force the equilibrium to the left. Additionally, theequilibrium can be affected in vivo by, for example, exposing compound17B to acid in the gut.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Watrers ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction scheme are set forthherein.

Examples of Kinase Inhibitors

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Compound 1:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid

N-(Dibenzylaminomethyl)benzotriazole: 1H-Benzotriazole-1-methanol (51.0g, 0.342 mol) was weighed into a round bottom flask and solubilized inEtOH (800 mL). Dibenzylamine (67.5 g, 0.342 mol) was added slowly (over5 min) to the rapidly stirred solution. Formation of a white precipitatewas observed shortly after starting addition. The solution was abandonedto stir for 24 h. At this time the reaction is judged complete by NMR(product fragments on LCMS to show only benzotriazole). The majority ofthe solvent was removed by rotovap and diethyl ether (1 L) was added tothe residue with vigorous stirring. This mixture was filtered, thefiltrand washed with ether and dried under vacuum to yield the desiredproduct as a fluffy white solid (112 g, quat. yield). ¹H NMR (400 MHz,chloroform-d) δ ppm 3.80 (s, 4H) 5.48 (s, 2H) 7.21 (d, J=8.34 Hz, 1H)7.34-7.43 (m, 11H) 7.49 (d, 1H) 8.09 (d, J=7.83 Hz, 1H).

Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate: To a suspension of zincdust (2.7 g, 41.6 mmol) in dry THF (75 mL), stirred under argonatmosphere, was added chlorotrimethylsilane (2.63 mL, 20.8 mmol)followed, 10 min later, by ethyl dibromo-fluoroacetate (3.92 g, 20.8mmol). After 10 min a slight exotherm was detected. The reaction wasleft to activate for 1 hour, whereupon it was cooled in an ice bath anda solution of N-(Dibenzylaminomethyl)benzotriazole (6.83 g, 20.8 mmol)in THF (50 mL) was added dropwise (over 30 minutes) and then thereaction mixture was allowed to warm to room temperature. After 18 h atr.t., NaHCO3 (sat., 50 mL) was added, let stir for 20 minutes, thereaction was filtered on Celite, and the filter pad was washed withEtOAc. The layers were separated and the aqueous phase was extractedwith EtOAc (3×50 mL). The organic layers were combined and washed with1N HCl (70 mL), brine (70 mL), then dried over MgSO₄. After evaporationof the solvent, the residue was poured into rapidly stirring ether (100mL); the solid formed was removed by filtration and discarded. The etherwas evaporated from the filtrate to yield a dark yellow syrup. Thiscrude residue was purified on silica gel column chromatographically(0-10% EtOAc:Hexanes) to yield the desired product as a clear liquid(3.6 g, 50% yield). ¹H NMR in CDCl₃: (400 MHz) δ ppm 1.18 (t, J=7.07 Hz,3H) 3.14 (t, J=13.26 Hz, 2H) 3.69 (s, 4H) 4.14 (q, J=7.16 Hz, 2H)7.14-7.33 (m, 10H). [M+H] calc'd for C₁₉H₂₁F₂NO₂, 334. found 334.

Ethyl 3-amino-2,2-difluoropropanoate-TFA salt: In a round bottom flask,Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.72 g, 5.2 mmol) wassolubilized in EtOH (25 mL) and TFA added (0.4 mL, 5.5 mmol). Under anatmosphere of nitrogen Pd(OH)₂/C (170 mg of 20% Pd by wt. wet) wasadded. The reaction mixture was repeatedly purged with nitrogen and thenleft under hydrogen overnight. At this point the reaction was deemedcomplete by LCMS, filtered through a pad of Celite, the pad washed withEtOH and the filtrate concentrated without heating to yield a foggysyrup which starts to crystallize upon standing (1.31 g, 94% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.29 (t, J=7.20 Hz, 3H) 3.72 (t, J=16.17Hz, 2H) 4.34 (q, J=7.24 Hz, 2H). [M+H] calc'd for C₅H₉F₂NO₂, 154. found154.

Ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate: To a round bottomflask was added Ethyl 3-amino-2,2-difluoropropanoate (1.31 g, 4.9 mmol),THF (50 mL), cyclopentanone (0.46 mL, 5.1 mmol), and NaOAc (400 mg, 4.9mmol). To this mixture was added sodium triacetoxyborohydride (1.6 g,7.3 mmol) portionwise over 15 minutes. The reaction was left to stirovernight. It was then added slowly to a stirring solution of ice (30mL), NaHCO₃ (sat., 10 mL), and EtOAc (100 mL) cooled in an ice-saltbath. The layers were then separated and the aqueous pH further adjustedto 11 using 25% NaOH while cooling in the bath. The aqueous layer waswashed with EtOAc (2×50 mL), the organic extracts combined, washed withcold NaHCO₃, (sat. 20 mL×2) brine (20 mL), dried over MgSO₄, filteredand concentrated to yield the desired product as a clear syrup (960 mg,89%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (t, J=7.07 Hz, 2H) 1.34-1.74(m, 8H) 3.00 (q, 1H) 3.11 (t, J=14.15 Hz, 2H) 4.27 (q, J=7.07 Hz, 2H).[M+H] calc'd for C₁₀H₁₇F₂NO₂, 222. found 222.

Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate:Compound Ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate (396 mg, 1.79mmol) was solubilized in acetone (40 mL, dry). The solution was cooledin an ice salt bath under a nitrogen atmosphere and K₂CO₃ (495 mg, 3.58mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (378mg, 1.97 mmol) in acetone (10 mL, dry) was added dropwise. Uponcompletion of addition the reaction mixture abandoned and allowed toslowly warm to room temperature and stir overnight. The mixture was thenfiltered through paper, the filter pad washed with acetone, and thefiltrate concentrated. The concentrate was then solubilized in EtOAc (10mL). Hexanes (70 mL) were then added and the solution was put on therotovap to slowly concentrate. Yellow crystals form and are collected byfiltration to yield 360 mg of the desired product Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate(53%). The filtrate was found to contain a 1:1:1 mixture of the product,dichloronitropyrimidine, and the 2-addition product. This material wasconcentrated and set aside for future use. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.22 (t, J=7.20 Hz, 3H) 1.36-1.98 (m, 8H) 3.64 (q, 1H) 4.25 (q,J=7.24 Hz, 2H) 4.35 (t, J=13.77 Hz, 2H) 8.94 (s, 1H). [M+H] calc'd forC₁₄H₁₇F₂N₄O₄, 379. found 379.

2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:Compound ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate(1.0 g, 2.7 mmol) was dissolved in AcOH (10 mL) and then cooled in anice bath. Iron powder (296 mg, 5.3 mmol) was added followed by the slowaddition of HCl (1.5 mL, conc.). After 10 minutes the reaction wastransferred to a heat bath and left to stir at 60° C. for 5 hours. Thereaction was then cooled, the stir bar and unreacted iron removed byfiltration through paper, and the solvent volume reduced by about 75% ona rotovap. The mixture was then diluted with ice water (15 mL) and EtOAc(20 mL), the layers separated, the aqueous layer washed with EtOAc (2×30mL), the organic extracts combined, washed with sat. NaHCO₃ (20 mL),brine (20 mL), dried over MgSO₄, filtered and concentrated to yield abrown syrup. Trituration with EtOAc (15 mL) and ether (100 mL) was usedto coax out a light yellow solid (535 mg, 65% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.41-1.96 (m, 8H) 3.98 (t, J=11.49 Hz, 2H) 4.87 (q, 1H)8.12 (s, 1H) 11.06 (br. s., 1H). [M+H] calc'd for C₁₂H₁₃ClF₂N₄O, 303.found 303.

2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(2.4 g, 7.95 mmol) was dissolved in DMA (20 mL) and cooled in an icebath. Sodium hydride (348 mg of 65% in mineral oil, 8.75 mmol) was addedslowly and left to stir for 10 minutes. Methyl iodide (0.546 mL, 8.75mmol) was then added and then after 10 minutes the solution removed fromthe bath. After 30 minutes the reaction was deemed complete by LCMS,poured into ice water (300 mL), the solution acidified with 1N HCl, theproduct filtered off as a yellow solid (2.36 g, 94% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.38-2.00 (m, 8H) 3.34 (s, 3H) 4.15 (t, J=13.26 Hz,2H) 4.80 (q, 1H) 8.35 (s, 1H). [M+H] calc'd for C₁₃H₁₅ClF₂N₄O, 317.found 317.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid:2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(2.77 g, 8.8 mmol), 4-amino-3-methoxy benzoic acid (1.61 g, 9.6 mmol),i-PrOH (30 mL) and conc. HCl (30 drops) were heated to 95° C. for 18hours. A this time the reaction was cooled to room temperature andfiltered to reveal the product as a tan solid (2.74 g, 70% yield). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 1.50-2.01 (m, 8H) 3.32 (s, 3H) 3.89 (s,3H) 4.04 (t, J=14.15 Hz, 2H) 4.75 (q, 1H) 7.50 (d, J=8.34 Hz, 1H) 7.52(s, 1H) 7.90 (s, 1H) 8.19 (d, J=8.34 Hz, 1H) 8.25 (s, 1H). [M+H] calc'dfor C₂₁H₂₃F₂N₅O₄, 447. found 447.

General Procedure for Amide Bond Synthesis

To a mixture of carboxylic acid (0.2 mmol), amine (0.3 mmol), DIEA(0.054 mL, 0.3 mmol) in 3 mL of anhydrous DMF was added HATU (114 mg,0.3 mmol). After 30 minutes the reaction mixture was either directlypurified by HPLC or diluted with ethyl acetate, washed with water andbrine, then organic layer dried over Na₂SO₄ and purified on HPLC. TheTFA salt obtained was then converted to its free base by washing withsat. NaHCO₃ solution.

Compound 2:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-cyclopropyl-3-methoxybenzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-propylamine. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.57 (dd, J=3.66, 2.40 Hz, 2H) 0.70 (dd, J=6.95, 2.15 Hz, 2H)1.50-1.77 (m, 6H) 1.88-1.97 (m, 2H) 2.82 (td, J=7.33, 3.54 Hz, 1H) 3.17(s, 3H) 3.92 (s, 3H) 3.99-4.08 (m, 3H) 4.75 (d, J=8.84 Hz, 1H) 7.40-7.51(m, 2H) 7.96 (s, 1H) 8.26 (d, J=8.34 Hz, 1H) 8.35 (d, J=4.04 Hz, 1H).[M+H] C₂₄H₂₈F₂N₆O₃ calc'd for, 487. found 487.

Compound 3:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.78 (m, 10H) 1.98 (m, 4H) 2.18 (s,3H) 2.79 (d, J=11.4 Hz, 2H) 3.33 (s, 3H) 3.74 (m, 1H) 3.94 (s, 3H) 4.04(t, J=14.0 Hz, 2H) 4.75 (q, J=7.9 Hz, 1H) 7.50 (s, 1H) 7.47 (d, J=1.5Hz, 1H) 7.94 (s, 1H) 8.09 (d, J=7.8 Hz, 1H) 8.27 (d, J=8.1 Hz, 1H) 8.26(s, 1H). [M+H] calc'd for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 4:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58-1.71 (m, 7H) 1.90 (m,3H) 2.42 (s, 3H) 3.32 (s, 3H) 3.76 (t, J=7.2 Hz, 2H) 3.94 (s, 3H) 4.05(t, J=13.8 Hz, 2H) 4.38-4.60 (m, 1H) 4.76 (d, J=7.8 Hz, 1H) 7.35-7.59(m, 2H) 7.99 (s, 1H) 8.26 (s, 1H) 8.29 (d, J=8.3 Hz, 1H) 8.72 (d, J=6.6Hz, 1H). Melting point: 157-162° C. [M+H] calc'd for C₂₅H₃₁F₂N₇O₃, 516.found 516.

Compound 5:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-amino piperidine 1-ethanol. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.44-2.07 (m, 12H) 2.38 (t, J=6.32 Hz, 2H)2.89 (d, J=11.37 Hz, 2H) 3.27-3.34 (s, 3H) 3.49 (q, J=6.06 Hz, 2H)3.65-3.83 (m, 1H) 3.93 (s, 2H) 3.97-4.14 (m, 2H) 4.37 (t, J=5.31 Hz, 1H)4.76 (t, J=7.83 Hz, 1H) 7.48 (d, J=8.0 Hz, 1H), 7.49 (br. s., 1H) 7.96(s, 1H) 8.12 (d, J=7.83 Hz, 1H)), 8.26 (s, 1H) 8.27 (d, J=8.0 Hz, 1H).[M+H] calculated for C₂₈H₃₇F₂N₇O₄, 574. found 574.

Compound 6:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-methylpiperazin-1-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.64 (m, 4H) 1.67-1.75 (m, 2H)1.89-1.97 (m, 2H) 2.79 (d, J=4.6 Hz, 3H) 3.11-3.30 (m, 6H) 3.32 (s, 3H)3.44 (d, J=12.6 Hz, 2H) 3.93 (s, 3H) 4.09 (t, J=13.9 Hz, 2H) 4.76-4.81(m, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.48 (s, 3H) 8.24 (d, J=8.34 Hz, 1H) 8.27(s, 1H) 9.79 (s, 1H). Melting point: 168-174° C. [M+H] calc'd forC₂₆H₃₄F₂N₈O₃, 545. found 545.

Compound 7:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-ethylpiperidin-1-amine. The final compound was purifiedby reverse phase HPLC and basified to give the free base. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.26 (t, J=7.2 Hz, 3H) 1.58-1.72 (m, 6H) 1.87-2.04(m, 6H) 2.96-3.06 (br. s., 4H) 3.32 (s, 3H) 3.47 (d, 2H) 3.94 (s, 3H)4.03 (m, 1H) 4.16 (t, J=13.4 Hz, 2H) 4.78-4.88 (m, 3H) 7.55 (dd, J=8.3,1.8 Hz, 3H) 7.59 (d, J=1.5 Hz, 1H) 8.13 (d, J=8.6 Hz, 1H) 8.30 (s, 1H)8.54 (d, J=7.3 Hz, 1H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₃, 558. found 558.

Compound 8:(R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-tert-butyl 3-aminopiperidine-1-carboxylate, where Bocwas removed using TFA in DCM. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.41-1.52 (m, 2H) 1.52-1.77 (m, 7H) 1.85-1.99 (m, 3H) 2.45 (t,J=9.9 Hz, 2H) 2.85 (d, J=12.4 Hz, 1H) 3.01 (dd, J=11.8, 3.4 Hz, 1H) 3.32(s, 3H) 3.85 (m, 1H) 3.94 (s, 3H) 4.05 (t, J=14.0 Hz, 3H) 4.76 (quin,J=8.2 Hz, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H) 7.97 (s, 1H) 8.04 (d,J=7.8 Hz, 1H) 8.26 (s, 1H) 8.28 (d, 1H). [M+H] calc'd for C₂₆H₃₃F₂N₇O₃,530. found 530.

Compound 9:(S)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-tert-butyl 3-aminopiperidine-1-carboxylate, where Bocwas removed using TFA in DCM. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.41-1.52 (m, 2H) 1.52-1.77 (m, 7H) 1.85-1.99 (m, 3H) 2.45 (t,J=9.9 Hz, 2H) 2.85 (d, J=12.4 Hz, 1H) 3.01 (dd, J=11.8, 3.4 Hz, 1H) 3.32(s, 3H) 3.85 (m, 1H) 3.94 (s, 3H) 4.05 (t, J=14.0 Hz, 3H) 4.76 (quin,J=8.2 Hz, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H) 7.97 (s, 1H) 8.04 (d,J=7.8 Hz, 1H) 8.26 (s, 1H) 8.28 (d, 1H). [M+H] calc'd for C₂₆H₃₃F₂N₇O₃,530. found 530.

Compound 10:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and tert-butyl 4-aminopiperidine-1-carboxylate, where Boc wasremoved using TFA in DCM. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.43 (qd, J=11.9, 3.8 Hz, 2H) 1.54-1.66 (m, 5H) 1.66-1.77 (m, 4H)1.98 (br. s, 2H) 2.52 (d, J=1.8 Hz, 2H) 2.98 (d, J=11.9 Hz, 2H)3.79-3.87 (m, 1H) 3.93 (s, 3H) 4.04 (t, J=14.2 Hz, 2H) 4.76 (quin, J=8.1Hz, 1H) 7.48 (d, 1H) 7.50 (s, 1H) 7.96 (s, 1H) 8.13 (d, J=8.1 Hz, 1H)8.26 (d, J=8.1 Hz, 1H) 8.26 (s, 1H). [M+H] calc'd for C₂₆H₃₃F₂N₇O₃, 530.found 530.

Compound 11:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamidein accordance with scheme 6 using 2-(dimethylamino)acetyl chloride. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.38 (dd, J=13.1, 4.0 Hz, 1H) 1.58 (m, 5H)1.71 (m, 2H) 1.83 (m, 2H) 1.93 (m, 2H) 2.21 (s, 5H) 2.52 (d, J=1.8 Hz,1H) 2.63-2.73 (m, 1H) 3.05 (t, J=12.1 Hz, 2H) 3.17-3.24 (m, 1H) 3.32 (s,5H) 3.93 (s, 3H) 4.05 (t, J=14.2 Hz, 3H) 4.36 (d, J=12.6 Hz, 1H) 4.77(q, J=8.3 Hz, 1H) 7.48 (dd, 1H) 7.50 (s, 1H) 7.97 (s, 1H) 8.17 (d, J=7.8Hz, 1H) 8.26 (s, 1H) 8.29 (d, 1H). [M+H] calc'd for C₃₀H₄₀F₂N₈O₄, 615.found 615.

Compound 12:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-4-yl)benzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-Boc-4-aminopiperidine. Further, after washing withwater (10 ml), t-butoxycarbonyl (Boc) protection group was removed using40% TFA in dichloromethane (6 ml). The resulting product was furtheracylated using 2-(pyrrolidin-1-yl)acetyl chloride. The title productusing preparative HPLC and neutralized with bicarbonate. ¹H NMR (400MHz, DMF) δ ppm 1.53-2.30 (m, 18H) 2.79-3.01 (m, 2H) 3.21-3.47 (m, 5H)4.17 (s, 3H) 4.21-4.41 (m, 6H) 4.59 (d, J=12.13 Hz, 1H) 5.00 (t, J=8.34Hz, 1H) 7.71 (d, J=1.77 Hz, 2H) 8.21 (s, 1H) 8.40 (d, J=7.83 Hz, 1H)8.50 (s, 2H). [M+H] calc'd for C₃₂H₄₂F₂N₈O₄, 641. found 641.

Compound 13:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-1-yl)benzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and pyrrolidin-1-amine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.43-1.75 (m, 6H) 1.90-2.02 (m, 2H) 2.67-3.03 (m,4H) 3.57 (s, 3H) 3.95 (s, 3H) 4.05 (t, 2H) 4.73-4.81 (m, 1H) 7.48-7.54(m, 2H) 8.00 (s, 1H) 8.20 (d, 1H) 8.27 (s, 1H) 8.30 (d, 1H). [M+H]calc'd for C₂₅H₃₁F₂N₇O₃, 516. found 516.

Compound 14:N-(Azepan-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and tert-butyl 4-aminoazepane-1-carboxylate, where Boc wasremoved using TFA in DCM. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.41-1.65 (m, 4H) 1.65-1.83 (m, 3H) 1.83-1.99 (m, 4H) 2.07 (m.,2H) 3.16 (s, 3H) 3.32 (s, 3H) 3.93 (s, 3H) 4.07 (t, J=13.8 Hz, 3H) 4.78(t, J=8.1 Hz, 1H) 7.41-7.54 (m, 2H) 8.14-8.29 (m, 2H) 8.31 (d, J=7.6 Hz,1H) 8.55 (br. s., 2H). [M+H] calc'd for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 15:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazepan-4-yl)benzamide

The title compound was synthesized by methylatingN-(Azepan-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamideusing methyl iodide. The final compound was purified by reverse phaseHPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.58-1.93 (m, 17H) 2.28 (br. s., 3H) 2.33 (br. s., 1H) 3.93 (s, 3H) 4.05(t, J=14.0 Hz, 3H) 4.75 (d, J=7.1 Hz, 1H) 7.37-7.53 (m, 2H) 7.96 (s, 1H)8.15 (d, J=7.8 Hz, 1H) 8.26 (t, J=4.0 Hz, 2H). [M+H] calc'd forC₂₈H₃₇F₂N₇O₃, 558. found 558.

Compound 16:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2-(methylamino)-2-oxoethyl)piperidin-4-yl)benzamide

2-(4-aminopiperidin-1-yl)-N-methylacetamide: To a solution of 2.0 g (10mmoles) of piperidine, which as dissolved in DMF, anhydrous, 100 mL, wasadded 2.8 g (20 mmoles) K₂CO₃, and 1.2 g (11 mmoles)2-chloro-N-methylacetamide. After stirring at 50° C. for overnight, themixture was diluted with 500 mL of EtOAc, washed with brine (3×500 mL),dried over Na₂SO₄, and solvent was evaporated in vacuum. The resultingresidue was treated with 50% TFA/DCM and was stirred at r.t. for 2 hrs,and solvent was evaporated in vacuum. The resulting mixture was purifiedby prep HPLC to give yellow oil, yield 1.5 g (88%). [M+H] calc'd forC₈H₁₇N₃O, 172. found 172.

4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2-(methylamino)-2-oxoethyl)piperidin-4-yl)benzamide:The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 2-(4-aminopiperidin-1-yl)-N-methylacetamide. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.86 (m, 11H) 1.95 (d,J=4.29 Hz, 2H) 2.15 (t, J=10.61 Hz, 2H) 2.62 (s, 3H) 2.81 (d, J=11.37Hz, 2H) 2.90 (s, 2H) 3.33 (s, 3H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H)4.77 (t, J=8.46 Hz, 1H) 7.43-7.53 (m, 2H) 7.57-7.69 (m, 1H) 7.97 (s, 1H)8.14 (d, J=7.58 Hz, 1H) 8.20-8.35 (m, 2H) [M+H] calc'd for C₂₉H₃₈F₂N₈O₄,601. found 601.

Compound 17:9-cyclopentyl-2-(4-(2-(dimethylamino)ethoxy)phenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized using an analogous procedure to thatdescribed in connection with4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid from2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-oneand 4-(2-(dimethylamino)ethoxy)aniline. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.44-1.79 (m, 6H) 1.93 (br. s, 2H) 2.20 (s, 6H) 2.59 (t, J=5.81 Hz, 2H)3.32 (s, Hz, 3H) 3.88-4.10 (m, 4H) 4.68 (t, J=8.34 Hz, 1H) 6.85 (d,J=8.84 Hz, 2H) 7.55 (d, J=9.09 Hz, 2H) 8.18 (s, 1H) 9.20 (s, 1H). [M+H]calc'd for C₂₃H₃₀F₂N₆O₂, 461. found 461.

Compound 18:6-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one

The title compound was synthesized using an analogous procedure to thatdescribed in connection with4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid from2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-oneand 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.48-1.80 (m, 6H) 1.95 (br. s, 2H) 3.40 (s, 3H) 4.01 (t, J=14.15Hz, 2H) 4.52 (s, 2H) 4.72 (t, J=8.08 Hz, 1H) 6.77 (d, J=8.34 Hz, 1H)7.20 (dd, J=8.59, 2.02 Hz, 1H) 7.46 (d, J=2.27 Hz, 1H) 8.20 (s, 1H) 9.35(s, 1H) 10.54 (br. s., 1H) [M+H] calc'd for C₂₁H₂₂F₂N₆O₃, 445. found445.

Compound 19:9-cyclopentyl-7,7-difluoro-5-methyl-2-(2-oxoindolin-6-ylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized using an analogous procedure to thatdescribed in connection with4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid from2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-oneand 6-aminoindolin-2-one. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.86(m, 6H) 1.92-2.16 (m, 2H) 3.39 (s, 3H) 3.54 (s, 2H) 3.87 (t, J=13.39 Hz,2H) 4.74 (quin, J=8.27 Hz, 1H) 6.81 (d, J=8.34 Hz, 1H) 7.00 (br. s., 1H)7.26 (s, 1H) 7.50 (br. s., 1H) 7.58 (s, 1H) 7.97 (s, 1H). [M+H] calc'dfor C₂₁H₂₂F₂N₆O₂, 429. found 429.

Compounds 20-30 were prepared as follows. A mixture of the2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(1 equiv.), the aniline (1.5 equiv.), the catalyst Pd(OAc)₂ (0.1equiv.), the ligand XANPHOS (0.2 equiv.) and Cs₂CO₃ (4 equiv.) weredissolved in dioxane and N,N-dimethyl acetamide (1: 1, 0.5 M). Thereaction mixture was subjected to microwave reaction at 160° C. for 30min. It was then poured to ice water, filtered through celite. Theaqueous filtrate was acidified with HCl, extracted three times withethyl acetate. The organic extracts were concentrated to a light yellowsolid, which was purified on HPLC. When having carboxylic acid on theanilines, the products obtained from Buchwald reactions were directlyused for next step amide bond formation reaction using HATU.

Compound 20:2-(1H-Indol-5-ylamino)-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was prepared using Buchwald reaction from2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-oneand 5-aminoindole. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (m, 4H) 1.69 (m,2H) 1.97 (m, 2H) 3.3 (s, 3H) 3.99 (t, J=14.3 Hz, 2H) 4.75 (t, J=8.0 Hz,1H) 6.29 (br. s., 1H) 7.18-7.41 (m, 3H) 7.96 (s, 1H) 8.18 (s, 1H) 9.16(s, 1H) 10.91 (br. s., 1H). [M+H] calc'd for C₂₁H₂₂F₂N₆O, 413. found413.

Compound 21:9-Cyclopentyl-7,7-difluoro-5-methyl-2-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-ylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was prepared using Buchwald reaction from2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-oneand 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.10-1.31 (m, 4H) 1.65 (m, 8H) 2.02 (m, 3H) 2.98(br. s., 2H) 3.46 (s, 3H) 4.02-4.25 (m, 2H) 4.88 (br. s., 2H) 6.26 (s,1H), 6.65 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.98 (s, 1H) 8.34 (d, J=8.0 Hz,1H) 8.45 (s, 1H). [M+H] calc'd for C₂₆H₂₉F₂N₇O, 494. found 494.

Compound 22:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluorobenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.50-1.75 (m, 12H) 1.99 (m, 3H) 2.19 (s, 3H)2.79 (m, 2H) 3.74 (m, 1H) 4.01 (t, J=14.0 Hz, 2H) 4.68 (m, 1H) 7.67 (d,J=8.6 Hz, 1H) 7.72 (d, J=12.4 Hz, 1H) 7.99 (t, J=8.2 Hz, 1H) 8.20 (d,J=7.3 Hz, 1H) 8.23 (s, 1H) 9.08 (s, 1H). [M+H] calc'd for C₂₆H₃₂F₃N₇O₂,532. found 532.

Compound 23:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.43-1.66 (m, 6H) 1.72 (m, 4H) 1.92-1.99 (m,5H) 2.15 (s, 3H) 2.76 (d, J=11.4 Hz, 2H) 3.71 (m, 1H) 4.04 (t, J=14.2Hz, 2H) 4.78 (t, J=7.8 Hz, 1H) 7.77 (s, 4H) 8.03 (d, J=7.6 Hz, 1H) 8.27(s, 1H) 9.67 (s, 1H). Melting point: 234-2350C. [M+H] calc'd forC₂₆H₃₃F₂N₇O₂, 514. found 514.

Compound 24:3-Chloro-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-chlorobenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.44-1.77 (m, 15H) 2.23 (s, 3H) 2.84 (m, 2H)3.96-4.07 (t, J=12 Hz, 2H) 4.66 (m, 1H) 7.80 (dd, J=8.5, 1.9 Hz, 1H)8.00 (d, J=1.8 Hz, 1H) 8.08 (d, J=8.6 Hz, 1H) 8.19-8.33 (m, 2H) 8.58 (s,1H). [M+H] calc'd for C₂₆H₃₂ClF₂N₇O₂, 548. found 548.

Compound 25:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethoxy)-benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluopromethylbenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.53-2.11 (m, 17H) 2.23 (s, 3H) 2.84 (m, 2H)4.02 (t, J=14.0 Hz, 2H) 4.66 (d, J=8.1 Hz, 1H) 7.77-7.92 (m, 2H) 8.13(d, J=8.6 Hz, 1H) 8.24 (s, 1H) 9.01 (s, 1H). [M+H] calc'd forC₂₇H₃₂F₅N₇O₃, 598. found 598.

Compound 26:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methylbenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.42-2.04 (m, 16H) 2.10-2.22 (m, 3H) 2.29 (s,3H) 2.77 (d, J=11.1 Hz, 2H) 3.72 (dd, J=7.3, 4.0 Hz, 1H) 3.98 (t, J=14.0Hz, 2H) 4.60 (t, J=8.2 Hz, 1H) 7.64 (d, J=8.3 Hz, 1H) 7.68-7.80 (m, 2H)8.08 (d, J=7.8 Hz, 1H) 8.19 (s, 1H) 8.60 (s, 1H). [M+H] calc'd forC₂₇H₃₅F₂N₇O₂, 528. found 528.

Compound 27:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethylbenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=8.0 Hz, 3H) 1.23-1.69 (m, 11H) 1.77(m, 4H) 1.99 (m, 2H) 2.20 (s, 3H) 2.69 (q, J=7.3 Hz, 2H) 3.75 (s, 1H)3.97 (t, J=14.2 Hz, 2H) 4.54 (t, J=8.1 Hz, 1H) 7.57-7.81 (m, 3H) 8.12(d, J=7.8 Hz, 1H) 8.17 (s, 1H) 8.61 (s, 1H). [M+H] calc'd forC₂₈H₃₇F₂N₇O₂, 542. found 542.

Compound 28:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluorobenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.44-1.74 (m, 11H) 1.86-2.09 (m, 5H) 2.15 (s,3H) 2.63-2.81 (m, 2H) 3.57-3.79 (m, 1H) 3.94-4.16 (m, 2H) 4.81 (t, J=8.1Hz, 1H) 7.32-7.46 (m, 1H) 7.51 (t, J=8.6 Hz, 1H) 7.85 (br. s., 1H) 7.88(dd, J=4.3, 2.3 Hz, 1H) 8.30 (s, 1H) 9.88 (s, 1H). [M+H] calc'd forC₂₆H₃₂F₃N₇O₂, 532. found 532.

Compound 29:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.41 (t, J=6.7 Hz, 3H) 1.60 (m, 6H) 1.74(m, 4H) 1.95 (m, 4H) 2.18 (s, 3H) 2.79 (d, J=10.6 Hz, 2H) 3.73 (m, 1H)4.05 (t, J=13.9 Hz, 2H) 4.19 (d, J=7.1 Hz, 2H) 4.74 (m, 1H) 7.40-7.59(m, 2H) 7.91 (s, 1H) 8.11 (d, J=7.6 Hz, 1H) 8.26 (m, 2H). [M+H] calc'dfor C₂₈H₃₇F₂N₇O₃, 558. found 558.

Compound 30:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethyl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-(trifluoromethyl)benzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.67 (m, 9H) 1.70-1.85 (m, 3H)2.13 (br. s., 1H) 2.27 (s, 3H) 2.84-2.93 (m, 1H) 3.32 (s, 3H) 3.74-3.86(m, 1H) 4.00 (t, J=14.0 Hz, 1H) 4.50 (quin, 1H) 7.96 (d, J=8.6 Hz, 1H)8.12 (dd, 1H) 8.20 (s, 1H) 8.21 (s, 1H) 8.48 (d, J=7.8 Hz, 1H) 8.52 (s,1H). [M+H] calc'd for C₂₇H₃₂F₅N₇O₂, 582. found 582.

Compound 31:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid

2-Fluoro-5-methoxy-4-nitrobenzoic acid: To a solution ofmethyl-2,5-difluoro-4-nitrobenzoate (10 g, 46 mmol) in methanol (100 mL)was added potassium hydroxide (7.73 g, 184 mmol) in two batches. Thereaction mixture was stirred in an oil bath at 80° C. for 1 h. It wasthen concentrated, acidified with HCl. Solid was filtered, washed withwater and dried to give the product as light yellow powder (10 g,quantitative yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (s, 3H) 7.66(d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H). [M+H] calc'd for C₈H₆FNO₅, 216.found 216.

4-Amino-2-fluoro-5-methoxybenzoic acid: A solution of2-fluoro-5-methoxy-4-nitrobenzoic acid (10 g, 46 mmol), HOAc (50 mL) andMeOH (50 mL) was hydrogenated using a hydrogen balloon overnight. Thesolution was then filtered through celite and concentrated to a residue,which was triturated with ether and ethyl acetate. The solid wasfiltered and dried to give the product as light yellow powder (8.3 g,98%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.76 (s, 3H) 5.88 (br s, 2H) 6.36(d, J=16 Hz, 1H) 7.13 (d, J=8 Hz, 1H) 12.32 (br s, 1H). [M+H] calc'd forC₈H₈FNO₃, 186. found 186.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid: Eleven batches of same scale reactions were carried out asfollows: A mixture of the chloropyrimidine (1.1 g, 3.48 mmol),4-amino-2-fluoro-5-methoxybenzoic acid (676 mg, 3.65 mmol), the catalystPd(OAc)₂ (78 mg, 0.35 mmol), the ligand XANTPHOS (405 mg, 0.7 mmol) andCs₂CO₃ (4.5 g, 13.9 mmol) were dissolved in dioxane and N,N-dimethylacetamide (1:3, 5 mL/15 mL, 0.2 M). The reaction mixture was subjectedto microwave reaction at 160° C. for 15 min. All of the eleven batchesof reaction mixtures were combined and poured to ice water, filteredthrough celite. The aqueous filtrate was acidified with HCl carefullyand stirred at rt. for 2 h. After which, solid was filtered, washed withwater. The dark solid was then dissolved in minimum amount of methanol,triturated with ethyl acetate and ether and concentrated to a slurrywhich was filtered and washed by ether to give a light tan solid (8.5g). The filtrate was then concentrated and trituated again to give asecond batch of solid (2.5 g). The final filtrate was purified byprep-HPLC to give another 500 mg of product. The total yield was 11.5 g(65%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (m, 3H) 1.73 (m, 2H)1.84-2.04 (m, 3H) 3.34 (s, 2H) 3.85-3.99 (m, 3H) 4.12 (t, J=13.8 Hz, 2H)4.84 (d, J=8.1 Hz, 2H) 7.38 (d, J=6.8 Hz, 1H) 8.27 (d, J=13.6 Hz, 1H)8.33 (s, 1H). [M+H] calc'd for C₂₁H₂₂F₃N₅O₄, 466. found 466.

Compound 32:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid

Ethyl 3-(cyclohexylamino)-2,2-difluoropropanoate: To a round bottomflask was added 4 (13.35 g, 50 mmol), THF (150 mL), cyclohexanone (5.89g, 60 mmol), and NaOAc (4.51 g, 55 mmol). To this mixture was addedsodium triacetoxyborohydride (15.90 g, 75 mmol) portion wise over 15minutes. The reaction was left to stir for 14 hrs. It was then cooled inan ice bath and sodium bicarbonate solution was added (100 mL, sat.)followed by EtOAc (200 ml). At this time the layers were separated andwashed the organic layer with more sat.NaHCO₃ (until aqueous layer PH isbasic ˜9). The aqueous layer was extracted with EtOAc (2×150 mL), theorganic extracts combined, washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to yield the desired product as acloudy syrup (9.94 g, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.77(m, 10H) 2.32 (m, 1H) 3.17 (t, J=16.0 Hz, 2H) 3.81 (s, 1H).

Ethyl4-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-3,3-difluoro-2-oxobutanoate:In a round bottom flask, ethyl3-(cyclohexylamino)-2,2-difluoropropanoate (11.05 g, 50 mmol) wasdissolved in acetone (100 mL), and added K₂CO₃ (13.8 g, 100 mmol) to it.Cooled the round bottom flask to 0° C. in an ice bath. After 20 min,added 2,4-dichloro 5-nitropyrimidine (9.70 g, 50 mmol) in acetone (25mL) dropwise and continued stirring for another 30 min at 0° C., thenallowed to warm up to room temperature, continued for 12 hrs. Thenevaporated the acetone washed with water and extracted into EtOAc (300mL) dried over Na₂SO₄ and evaporated. The crude gummy solid was purifiedon Combiflash (ISCO) using hexane-EtOAc as solvent system to obtain thedesired compound (11.85 g, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.02-1.31 (m, 3H) 1.42-1.68 (m, 3H) 1.75 (d, J=9.09 Hz, 4H) 3.33 (m, 1H)3.80 (s, 3H) 4.40 (t, J=14.02 Hz, 2H) 8.92 (s, 1H). MS (ES) [M+H]calculated for C₁₅H₁₉ClF₂N₄O₄, 393. found 393.

2-Chloro-9-cyclohexyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:In a round bottom flask compound ethyl4-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-3,3-difluoro-2-oxobutanoate(11.85 g, 31.35 mmol) was dissolved in acetic acid (30 mL), and addediron powder (3.51 g, 62.7 mmol) to it. Then cooled the round bottomflask to 0° C. in an ice bath. After 10 min, added conc.HCl (12 mL)dropwise using addition funnel and continued the reaction at 60° C. on apreheated oil bath until starting material disappear. It was thenconcentrated in vacuo, diluted with EtOAc, basified with 10% NaOHsolution at 0° C. The whole was filtered through celite, washed withEtOAc. The filtrate was then separated. The organic layer was dried overNa₂SO₄. The solution was concentrated in vacuo followed by precipitationfrom ether to afford the desired compound (6.0 g, 62% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96-1.85 (m, 10H) 4.02 (t,J=11.37 Hz, 2H) 4.47 (m, 1H) 8.11 (s, 1H) 11.02 (br. s., 1H). [M+H]calc'd for C₁₃H₁₅ClF₂N₄O, 317. found 317.

2-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:To a solution of compound2-Chloro-9-cyclohexyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(6.0 g, 18.98 mmol) in 30 mL of DMA was added sodium hydride (60%dispersion in mineral oil, 1.138 g, 28.47 mmol) at 0° C., followed bythe dropwise addition of methyl iodide (1.42 mL, 22.78 mmol). Thereaction mixture was warmed up to rt and stirred for 1 h. The whole waspoured into ice-water, extracted with ethyl acetate. The organic layerwas washed with brine and dried over Na₂SO₄. The solution wasconcentrated in vacuo followed by precipitation from ether/EtOA toafford the desired compound (3.0 g, 47.9% yield) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.97-1.85 (m, 10H) 3.33 (s, 3H) 4.15 (t,J=12.88 Hz, 2H) 4.44 (m, 1H) 8.31 (s, 1H). [M+H] calc'd forC₁₄H₁₇ClF₂N₄O, 331. found 331.

4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid:2-Chloro-9-cyclohexyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(2.77 g, 8.8 mmol), 4-amino-3-methoxy benzoic acid (1.61 g, 9.6 mmol),i-PrOH (30 mL) and conc. HCl (30 drops) were heated to 95° C. for 18hours. A this time the reaction was cooled to room temperature andfiltered to reveal the product as a tan solid (2.74 g, 70% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, J=12.13 Hz, 1H) 1.23-1.42 (m, 2H)1.53-1.78 (m, 5H) 1.82 (d, J=12.63 Hz, 2H) 3.32 (s, 3H) 3.94 (s, 3H)4.26 (t, J=12.38 Hz, 2H) 4.52 (t, J=11.62 Hz, 1H) 7.47-7.65 (m, 2H) 8.13(d, J=8.08 Hz, 1H) 8.28-8.45 (m, 1H) 9.43 (br. s., 1H). [M+H] calc'd forC₂₂H₂₅F₂N₅O₄, 462. found 462.

Compound 33:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-amino 4-methylpiperidine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.19-1.26 (m, 2H) 1.39 (m, 2H) 1.50-1.71(m, 5H) 1.78-1.85 (m, 6H) 1.96 (t, J=10.9 Hz, 2H) 2.18 (s, 3H) 2.79 (d,J=10.6 Hz, 2H) 3.94 (s, 3H) 4.05 (t, J=13.2 Hz, 2H) 4.46 (m., 1H) 7.48(d, J=8.3 Hz, 1H) 7.51 (br. s., 1H) 7.89 (s, 1H) 8.10 (d, J=7.6 Hz, 1H)8.21 (s, 1H) 8.26 (d, J=8.1 Hz, 1H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₃, 558.found 558.

Compound 34:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-amino 4-methylpiperazine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.85 (m, 10H) 2.18 (s, 3H) 2.93 (br.s., 3H) 3.22-3.47 (m, 7H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m,1H) 7.44 (br. s., 1H) 7.42 (d, J=8.84 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H)8.27 (d, J=8.08 Hz, 1H) 9.40 (s, 1H). [M+H] calculated for C₂₇H₃₆F₂N₈O₃,559. found 559.

Compound 35:4-(9-Cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18-1.82 (m, 12H) 2.32 (s,3H) 3.10 (s, 3H) 3.62 (s, 2H) 3.95 (s, 3H) 4.06 (t, J=13.4 Hz, 2H) 4.47(m, 1H) 4.45 (d, J=6.8 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H) 7.53 (s, 1H) 7.90(s., 1H) 8.21 (s, 1H) 8.28 (d, J=8.1 Hz, 1H) 8.65 (d, J=5.8 Hz, 1H).[M+H] calc'd for C₂₆H₃₃F₂N₇O₃, 530. found 530.

Compound 36:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-(3-aminopropyl)pyrrolidin-2-one. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (t,J=7.07 Hz, 3H) 1.17 (m, 2H) 1.35-1.80 (m, 12H) 2.32 (q, J=7.07 Hz, 2H)2.87 (br. d., 2H) 3.33 (s, 3H) 3.76 (m, 1H) 3.94 (s, 3H) 4.06 (t,J=13.64 Hz, 2H) 4.46 (m, 1H) 7.47 (d, J=8.59 Hz, 1H) 7.50 (s, 1H) 8.14(d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculated forC₂₉H₃₉F₂N₇O₃, 572. found 572.

Compound 37:(S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-1-Boc-3-aminopiperidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml) andpurified the product using preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.08-1.95 (m., 14H) 2.40 (t, J=7.38 Hz, 2H) 2.80 (br. s., 1H) 2.96(br. s., 1H) 3.33 (s, 3H) 3.81 (br. s., 1H) 3.94 (s, 3H) 4.06 (t,J=13.64 Hz, 2H) 4.45 (m, 1H) 7.34-7.55 (m, 2H) 7.90 (s, 1H) 8.03 (d,J=7.58 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculatedfor C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 38:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-Boc-3-aminopiperidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml) andpurified the product using preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.15-1.95 (m., 14H) 2.52 (t, J=7.38 Hz, 2H) 2.92 (br. d., 1H) 3.07(br. d., 1H) 3.39 (s, 3H) 3.81 (br. s., 1H) 3.94 (s, 3H) 4.06 (t,J=13.64 Hz, 2H) 4.45 (m, 1H) 7.34-7.55 (m, 2H) 7.90 (s, 1H) 8.03 (d,J=7.58 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculatedfor C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 39:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpyrrolidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methyl-3-(R)-amino pyrrolidine dihydrochloride. Thefinal compound was purified by reverse phase HPLC and basified to givethe free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.90 (m, 12H) 2.18(m, 1H) 2.26 (s, 3H) 2.32-2.56 (m, 2H) 2.60-2.68 (m, 2H) 3.34 (s, 3H)3.95 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.34-4.54 (m, 2H) 7.51 (d, J=8.0Hz, 1H), 7.54 (br. s., 1H) 7.90 (s, 1H), 8.21 (s, 1H) 8.27 (d, J=8.0 Hz,1H) 8.40 (br. s., 1H). Melting point: 98-99° C. [M+H] calculated forC₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 40:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and trans-4-aminocyclohexanol. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.69 (m, 12H) 1.83 (br. m., 6H) 3.34(s, 3H) 3.72 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.14 Hz, 2H) 4.45 (m, 1H)4.59 (br s., 1H) 7.47 (d, J=8.0 Hz, 1H), 7.51 (br. s., 1H) 7.89 (s, 1H),8.10 (br d., 1H) 8.21 (s, 1H) 8.25 (d, J=8.3 Hz, 1H). [M+H] calculatedfor C₂₈H₃₆F₂N₆O₄, 559. found 559.

Compound 41:(1R,4R)-4-(4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)cyclohexyldihydrogen phosphate

Di-tert-butyl(1R,4R)-4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)cyclohexyl phosphate:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((1r,4r)-4-hydroxycyclohexyl)-3-methoxybenzamide(214 mg, 0.383 mmol) was suspended in DMA (4 mL) and treated withtetrazole (3% wt in water, 4.50 mL, 1.53 mmol) and di-tert-butyldiethylphosphoramidite (0.23 mL, 0.827 mmol). The reaction mixture wasstirred at ambient temperature for 16 h, cooled to −10° C. and treatedwith hydrogen peroxide (30% aqueous, 0.3 mL). It was then stirred atroom temperature for 16 h and another portion of hydrogen peroxide wasadded (30%, 0.3 mL) and stirred for 3 h. A solution of Na₂S₂O₅ (500 mg)in water (5 mL) was then added slowly at 0° C., the reaction mixture wasstirred for 2 h and poured dropwise into a mixture of NaHCO₃ (sat. aq.,25 mL) and water (25 mL) with stirring. The resulting precipitate wasstirred vigorously until a fine suspension resulted and the precipitatewas filtered and purified by HPLC (acetonitrile-water, buffered with 10mM NH₄HCO₃) to afford the title compound as a white solid (42.0 mg,15%). [M+H] calc'd for C₃₆H₅₃F₂N₆O₇P, 751. found 751.5.

(1R,4R)-4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)cyclohexyldihydrogen phosphate: Di-tert-butyl(1r,4r)-4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)cyclohexylphosphate (42.0 mg, 0.0560 mmol) was dissolved in dichloromethane (1 mL)and methanol (0.2 mL) and treated with HCl (4N, dioxane, 1 mL). Thereaction mixture was stirred for 4 h and concentrated in vacuo. Thecrude material was suspended in acetonitrile, stirred vigorously for 20min and the resulting fine solid was filtered, and dried in vacuum toafford the title compound a white solid (23.0 mg, 64%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10-1.37 (m, 3H) 1.37-1.53 (m, 4H) 1.56-1.69 (m, 3H)1.68-1.77 (m, 2H) 1.77-1.95 (m, 4H) 1.98-2.07 (m, 2H) 3.31 (s, 3H)3.71-3.83 (m, 1H) 3.94 (s, 3H) 3.98-4.11 (m, 1H) 4.20 (t, J=12.88 Hz,2H) 4.43-4.54 (m, 1H) 7.50 (dd, J=8.34, 1.77 Hz, 1H) 7.56 (d, J=1.52 Hz,1H) 8.06 (d, J=8.34 Hz, 1H) 8.20 (d, J=7.58 Hz, 1H) 8.26 (s, 1H). [M+H]calc'd for C₂₈H₃₇F₂N₆O₇P, 639. found 639.

Compound 42:N-(azepan-4-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N—Boc-hexahydro azepine 4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml) andpurified the product using preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.10-2.05 (m, 16H) 2.88 (d, J=3.28 Hz, 1H) 3.01 (br. s., 2H) 3.31(s, 3H) 3.34 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.26 Hz, 3H) 4.46 (m,1H) 7.47 (d, J=8.1 Hz, 1H) 7.50 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H)8.23-8.30 (m, 2H). [M+H] calculated for C₂₈H₃₇F₂N₇O₃, 558. found 558.

Compound 43:N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N—Boc 3-amino azetidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml) andpurified the product using preparative HPLC. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.22-1.85 (m, 10H) 3.32 (s, 3H) 3.35-3.41 (m, 1H) 3.79 (br. s., 2H)3.95 (s, 3H) 4.01-4.11 (m, 4H) 4.47 (m, 1H) 7.45-7.58 (m, 2H) 7.93 (s,1H) 8.22 (s, 1H) 8.30 (d, J=8.1 Hz, 1H) 8.86 (br. d., 1H). [M+H]calculated for C₂₅H₃₁F₂N₇O₃, 516. found 516.

Compound 44:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 2-(4-aminopiperidin-1-yl)ethanol. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.20 (m, 1H) 1.39 (m, 3H) 1.54-1.90 (m,10H) 2.02 (t, J=10.99 Hz, 2H) 2.38 (t, J=6.32 Hz, 2H) 2.89 (d, J=10.86Hz, 2H) 3.31 (s, 3H) 3.49 (br. s., 2H) 3.74 (m, 1H) 3.94 (s, 3H) 4.06(t, J=13.39 Hz, 2H) 4.45 (m, 2H) 7.47 (d, J=8.0 Hz, 1H) 7.51 (s, 1H)7.90 (s, 1H) 8.14 (d, J=8.0 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H).[M+H] calculated for C₂₉H₃₉F₂N₇O₄, 588. found 588.

Compound 45:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-(+)-3-aminoquinuclidine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.43 (m, 3H) 1.57-1.92 (m, 12H) 2.69(d, J=6.57 Hz, 2H) 2.71 (m, 3H) 2.89 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H)3.95 (s, 3H) 3.97-4.16 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.49(s, 1H) 7.93 (s, 1H) 8.14 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H).[M+H] calculated for C₂₉H₃₇F₂N₇O₃, 570. found 570.

Compound 46:(S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-(−)-3-aminoquinuclidine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.42 (m, 3H) 1.57-1.92 (m, 12H)2.71-89 (m, 4H) 2.96 (m, 1H) 3.13 (m, 1H) 3.31 (s, 3H) 3.95 (s, 3H)3.97-4.10 (m, 2H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.93(s, 1H) 8.19 (d, 1H) 8.21 (s, 1H) 8.26 (d, J=8.0 Hz, 1H). [M+H]calculated for C₂₉H₃₇F₂N₇O₃, 570. found 570.

Compound 47:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((cis)-2-hydroxycyclohexyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and cis-(±)-2-aminocyclohexanol. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.93 (m, 18H) 3.31 (s, 3H) 3.73-3.91(m, 2H) 3.95 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.47 (m, 1H) 4.70 (br. s.,1H) 7.47 (d, J=8.0 Hz, 1H) 7.53 (s, 1H) 7.79 (d, J=7.83 Hz, 1H) 7.90 (s,1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H). [M+H] calculated forC₂₈H₃₆F₂N₆O₄, 559. found 559.

Compound 48:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-((trans)-2-hydroxycyclohexyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and trans-(±)-2-aminocyclohexanol. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.93 (m, 18H) 3.32 (s, 1H) 3.45 (m,1H) 3.64 (m, 1H) 3.95 (s, 3H) 4.07 (t, J=13.39 Hz, 2H) 4.48 (m, 1H) 4.64(br. s., 1H) 7.49 (d, J=8.0 Hz, 1H) 7.55 (s, 1H) 7.90 (s, 1H) 8.03 (d,J=8.08 Hz, 1H) 8.22 (s, 1H) 8.28 (d, J=8.34 Hz, 1H). [M+H] calculatedfor C₂₈H₃₆F₂N₆O₄, 559. found 559.

Compound 49:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(dimethylamino)cyclohexyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N1,N1-dimethylcyclohexane 1,4-diamine. The final compoundwas purified by reverse phase HPLC and basified to give the free base.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.96 (m, 18H) 2.17 (s, 6H) 3.31 (s,3H) 3.73 (m, 1H) 3.92 9m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.46(m, 1H) 7.42-7.59 (m, 2H) 7.89 (s, 1H) 8.11 (m, 1H) 8.21 (s, 1H) 8.26(d, J=8.34 Hz, 1H). Melting point: 208-214° C. [M+H] calculated forC₃₀H₄₁F₂N₇O₃, 586. found 586.

Compound 50:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N-(2,2,2-trifluoroethyl)piperidin-4-amine. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.44 (m, 4H) 1.55-1.89(m, 10H) 2.42 (t, J=8.0 Hz, 2H) 2.94 (br. d., 2H) 3.17 (q, J=10.11 Hz,2H) 3.31 (s, 3H) 3.78 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 7.47(d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.91 (s, 1H) 8.15 (d, J=8.02 Hz, 1H) 8.21(s, 1H) 8.27 (d, J=8.34 Hz, 1H). Melting point: 213-215° C. [M+H]calculated for C₂₉H₃₆F₅N₇O₃, 626. found 626.

Compound 51:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 8-methyl-8-azabicyclo[3.2.1]octan-3-aminedihydrochloride. The final compound was purified by reverse phase HPLCand basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.13-1.45 (m, 4H) 1.37-1.85 (m, 12H) 1.99 (s, 2H) 2.29 (br. s., 2H) 3.31(s, 3H) 3.93 (s, 3H) 3.97-4.22 (m, 3H) 4.45 (m, 1H) 7.47 (d, J=8.0 Hz,1H) 7.49 (s, 1H) 7.90 (s, 1H) 8.15 (d, 1H) 8.20 (s, 1H) 8.25 (d, J=8.34Hz, 1H). [M+H] calculated for C₃₀H₃₉F₂N₇O₃, 584. found 584.

Compound 52:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-cyclopentylpiperazin-1-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N-cyclopentyl piperazine-4-amine. The final compoundwas purified by reverse phase HPLC and basified to give the free base.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.92 (m, 18H) 2.93 (br. s., 4H)3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.44 (m, 1H) 7.41 (d,J=8.0 Hz, 1H) 7.43 (s, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz,1H) 9.37 (s, 1H). Melting point: 98-99° C. [M+H] calculated forC₃₁H₄₂F₂N₈O₃, 613. found 613.

Compound 53:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-(dimethylamino)ethyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N,N-dimethylethylenediamine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.27 (m, 2H) 1.27-1.51 (m, 2H)1.51-1.86 (m, 6H) 2.17 (s, 6H) 2.39 (t, J=7.8 Hz, 2H) 3.31 (s, 3H) 3.38(m, 2H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.48 (d,J=8.0 Hz, 1H) 7.52 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.34 Hz,1H) 8.35 (br. s., 1H). [M+H] calculated for C₂₆H₃₅F₂N₇O₃, 532. found532.

Compound 54:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-(dimethylamino)propyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N,N-dimethyl-1,3-propanediamine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.49 (m, 3H) 1.53-1.87 (m., 9H) 2.13(s, 6H) 2.25 (t, J=6.44 Hz, 2H) 3.29 (m, 2H) 3.31 (s, 3H) 3.93 (s, 3H)4.06 (t, J=13.26 Hz, 2H) 4.46 (m, 1H) 7.46 (d, J=8.0 Hz, 1H) 7.51 (s,1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.08 Hz, 1H) 8.48 (br. s., 1H).[M+H] calculated for C₂₇H₃₇F₂N₇O₃, 546. found 546.

Compound 55:N-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N—Boc 3-amino azetidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml) andthe final compound was purified by reverse phase HPLC and basified togive the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.28 (m, 1H)1.33-1.46 (m, 2H) 1.59-1.66 (m, 2H) 1.75-1.87 (m, 4H) 3.32 (s, 3H)3.67-3.80 (m, 4H) 3.95 (s, 3H) 4.07 (t, 2H) 4.4-4.5 (m, 1H) 4.65-4.83(m, 1H) 7.50 (d, J=8.3 Hz, 1H) 7.54 (d, J=1.5 Hz, 1H) 7.93 (s, 1H) 8.21(s, 1H) 8.29 (d, J=8.1 Hz, 1H) 8.81 (d, J=6.8 Hz, 1H). [M+H] calc'd forC₂₅H₃₁F₂N₇O₃ 516. found 516.

Compound 56:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 2-(pyrrolidin-1-yl)ethanamine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.22 (m, 1H) 1.38 (m, 2H) 1.65 (t, J=13.1Hz, 3H) 1.79-1.92 (m, 6H) 2.03 (m, 2H) 3.08 (m, 2H) 3.33 (s, 3H) 3.35(d, J=5.8 Hz, 2H) 3.61 (m, 4H) 3.96 (s, 3H) 4.12 (t, J=13.0 Hz, 2H)4.40-4.58 (m, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.56 (s, 1H) 8.22 (s, 1H) 8.24(d, J=1.3 Hz, 1H) 8.29 (d, J=7.8 Hz, 1H) 8.7 (dd, J=10.1, 1.3 Hz, 1H).[M+H] calc'd for C₂₈H₃₇F₂N₇O₃ 558. found 558.

Compound 57:9-cyclohexyl-7,7-difluoro-2-(2-methoxy-4-(4-methylpiperazine-1-carbonyl)-phenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N-methylpiperazine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.27-1.35 (m, 2H) 1.54-1.67 (m, 3H) 1.72-1.84 (m, 5H)2.83 (s, 3H) 3.31 (d, J=3.2 Hz, 3H) 3.91 (d, J=4.6 Hz, 3H) 3.95-4.33 (m,10H) 4.39-4.54 (m, 1H) 7.06 (dd, J=8.1, 2.0 Hz, 1H) 7.13 (d, J=110 Hz,1H) 8.10-8.18 (m, 1H) 8.22 (d, J=3.0 Hz, 1H). [M+H] calc'd forC₂₇H₃₅F₂N₇O₃ 544. found 544.

Compound 58:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and ammonium chloride. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.10-1.41 (m, 3H) 1.54-1.86 (m, 7H) 3.32 (s, 3H) 3.93 (s,3H) 4.17 (t, J=12.5 Hz, 2H) 4.44-4.55 (m, 1H) 7.33 (s, 1H) 7.55 (d,J=8.3 Hz, 1H) 7.59 (s, 1H) 7.99 (s, 1H) 8.13 (d, J=8.1 Hz, 1H) 8.24 (s,1H) 8.61 (s, 1H). [M+H] calc'd for C₂₂H₂₆F₂N₆O₃ 461. found 461.

Compound 59:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-(dimethylamino)propyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N,N-dimethyl-1,3-propanediamine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.30 (m, 2H) 1.43-1.57 (m, 3H)1.58-1.80 (m, 2H) 2.67 (m, 6H) 2.91-3.01 (m, 2H) 3.20 (br.s., 3H) 3.22(m, 2H) 3.82 (s, 3H) 4.02 (t, J=13.0 Hz, 2H) 4.36 (quin., 1H) 7.39 (d,J=6.1 Hz, 1H) 7.43 (br. s., 1H) 8.09 (d, J=8.8 Hz, 1H) 8.10-8.13 (m, 1H)8.31 (br. s., 1H) 8.50 (br. s., 1H). [M+H] calc'd for C₂₇H₃₇F₂N₇O₃ 546.found 546.

Compound 60:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methylbenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and methylamine. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.13-1.42 (m, 2H) 1.52-1.91 (m, 8H) 2.80 (d, 3H) 3.94 (s, 3H) 4.16(t, 2H) 4.49 (quin, 1H) 7.50 (d, 1H) 7.55 (s, 1H) 8.14 (d, J=8.1 Hz, 1H)8.24 (d, J=2.0 Hz, 1H) 8.42 (d, J=4.3 Hz, 1H) 8.58 (br. s., 1H). [M+H]calc'd for C₂₃H₂₈F₂N₆O₃ 475. found 475.

Compound 61:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N′,N′-dimethylbenzohydrazide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and N,N-dimethyl-hydrazine. The final compound was purifiedby reverse phase HPLC and basified to give the free base. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.15-1.43 (m, 2H) 1.53-1.92 (m, 8H) 2.92 (s, 6H)3.32 (s, 3H) 3.96 (s, 3H) 4.14 (t, J=13.0 Hz, 2H) 4.42-4.52 (m, 1H)7.44-7.52 (m, 2H) 8.20-8.27 (m, 2H) 8.49 (br. s., 1H). [M+H] calc'd forC₂₄H₃₁F₂N₇O₃ 504. found 504.

Compound 62:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-1-aminopropan-2-ol. The final compound was purifiedby reverse phase HPLC and basified to give the free base. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.1 Hz, 3H) 1.12-1.41 (m, 3H) 1.55-1.87(m, 8H) 1.70-1.88 (m, 4H) 3.21 (q, J=6.3 Hz, 1H) 3.32 (s, 3H) 3.77 (m,1H) 3.94 (s, 3H) 4.16 (t, J=13.0 Hz, 2H) 4.49 (quin., J=12.1 Hz, 1H)7.53 (d, J=8.6 Hz, 1H) 7.58 (s, 1H) 8.14 (d, J=8.3 Hz, 1H) 8.23 (s, 1H)8.41-8.47 (m, 1H) 8.51-8.57 (m, 1H). [M+H] calc'd for C₂₅H₃₂F₂N₆O₄ 519.found 519.

Compound 63:(S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-hydroxypropyl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-aminopropan-2-ol. The final compound was purifiedby reverse phase HPLC and basified to give the free base. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.1 Hz, 3H) 1.12-1.41 (m, 3H) 1.55-1.87(m, 8H) 1.70-1.88 (m, 4H) 3.21 (q, J=6.3 Hz, 1H) 3.32 (s, 3H) 3.77 (m,1H) 3.94 (s, 3H) 4.16 (t, J=13.0 Hz, 2H) 4.49 (quin., J=12.1 Hz, 1H)7.53 (d, J=8.6 Hz, 1H) 7.58 (s, 1H) 8.14 (d, J=8.3 Hz, 1H) 8.23 (s, 1H)8.41-8.47 (m, 1H) 8.51-8.57 (m, 1H). [M+H] calc'd for C₂₅H₃₂F₂N₆O₄ 519.found 519.

Compound 64:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-1-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and piperidin-1-amine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.15-1.90 (m, 16H) 3.16 (br. s., 6H) 3.32 (s, 3H) 3.96(s, 3H) 4.14 (t, 2H) 4.48 (quin, 1H) 7.47 (d, 1H) 7.49 (s, 1H) 8.22 (d,1H) 8.24 (s, 1H) 8.47 (br. s., 1H). [M+H] calc'd for C₂₇H₃₅F₂N₇O₃ 544.found 544.

Compound 65:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-morpholinobenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and morpholin-4-amine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.12-1.41 (m, 2H) 1.59-1.86 (m, 8H) 2.94 (br. s., 4H)3.31 (s, 3H) 3.67 (br. s., 4H) 3.94 (s, 3H) 4.16 (t, 2H) 4.38-4.54 (m,1H) 7.45 (d, J=8.7 Hz, 1H) 7.48 (s, 1H) 8.14 (d, 1H) 8.23 (s, 1H) 8.57(br. s., 1H) 9.57 (s, 1H). [M+H] calc'd for C₂₆H₃₃F₂N₇O₄ 546. found 546.

Compound 66:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and tetrahydro-2H-pyran-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.43 (m, 3H) 1.49-1.90 (m, 11H)3.19-3.32 (m, 3H) 3.32-3.46 (m, 2H) 3.84-3.92 (m, 2H) 3.94 (d, J=9.0 Hz,3H) 3.97-4.08 (m, 1H) 4.07-4.23 (m, 2H) 4.38-4.58 (m, 1H) 7.42-7.61 (m,2H) 8.06-8.17 (m, 1H) 8.24 (br. s., 2H) 8.62 (br. s., 1H). [M+H] calc'dfor C₂₇H₃₄F₂N₆O₄ 545. found 545.

Compound 67:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-1-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and pyrrolidin-1-amine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.12-1.45 (m, 3H) 1.55-1.90 (m, 7H) 2.02 (br. s., 4H)3.33 (s, 3H) 3.52 (br. s., 4H) 3.97 (s, 3H) 4.14 (t, 2H) 4.49 (quin, 1H)7.48 (d, 1H) 7.52 (s, 1H) 8.26 (s, 1H) 8.31 (d, 1H) 8.42 (s, 1H). [M+H]calc'd for C₂₆H₃₃F₂N₇O₃ 530. found 530.

Compound 68:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-(methylsulfonyl)piperidin-4-amine. The final compoundwas purified by reverse phase HPLC and basified to give the free base.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.35 (m, 3H) 1.47-1.90 (m, 11H)2.75-2.80 (m, 1H) 2.82 (s, 3H) 3.25 (s, 3H) 3.79-3.86 (m, 1H) 3.88 (s,3H) 4.08 (t, 1H) 4.36-4.47 (m, 1H) 7.43 (dd, J=8.6, 1.77 Hz, 1H) 7.47(d, J=1.8 Hz, 1H) 8.09 (d, J=8.3 Hz, 1H) 8.16 (s, 1H) 8.22 (d, 1H) 8.41(br. s., 1H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₅S 622. found 622

Compound 69:N-(1-acetylazetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-(3-aminoazetidin-1-yl)ethanone. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=12.4 Hz, 1H) 1.34-1.45 (bq, 2H)1.57-1.68 (m, 3H) 1.78 (s, 3H) 1.84 (m, 3H) 3.32 (s, 3H) 3.88 (m, 1H)3.95 (s, 3H) 4.03-4.12 (m, 4H) 4.42 (t, J=8.2 Hz, 1H) 4.45-4.51 (m, 1H)4.68 (q, J=6.8 Hz, 3H) 7.51 (dd, J=8.3, 1.8 Hz, 1H) 7.54 (d, J=1.5 Hz,1H) 7.93 (s, 1H) 8.22 (s, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.89 (d, J=6.8 Hz,1H). [M+H] calc'd for C₂₇H₃₃F₂N₇O₄ 558. found 558.

Compound 70:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-N—Boc 4-amino piperidine. Further, after washing withwater (10 ml), t-butoxycarbonyl (Boc) protection group was removed using40% TFA in dichloromethane (6 ml). The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.11-1.27 (m, 1H) 1.30-1.51 (m, 4H) 1.52-1.69 (m, 3H)1.69-1.90 (m, 6H) 2.41-2.59 (m, 2H) 2.97 (d, J=12.38 Hz, 2H) 3.31 (s,3H) 3.73-3.89 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H) 4.38-4.52(m, 1H) 7.48 (dd, J=8.34, 1.77 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.90 (s,1H) 8.14 (d, J=7.83 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H]calc'd for C₂₇H₃₅F₂N₇O₃ 544. found 544.

Compound 71:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamideand 2-(dimethylamino)acetyl chloride. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.14-1.25 (m, 1H) 1.33-1.46 (m, 3H) 1.48-1.65 (m, 3H)1.72-1.90 (m, 6H) 2.35 (s, 6H) 2.72 (t, J=12.2 Hz, 1H) 2.72 (t, 1H) 3.10(t, J=11.8 Hz, 1H) 3.31 (s, 3H) 3.47 (d, 1H) 3.94 (s, 3H) 4.06 (t,J=13.5 Hz, 2H) 3.97-4.12 (m, 2H) 4.35 (d, 1H) 4.46 (br. s., 1H) 7.47(dd, J=8.4, 1.6 Hz, 1H) 7.50 (d, J=1.7 Hz, 1H) 7.91 (s, 1H) 8.19 (d,J=8.1 Hz, 1H) 8.21 (s, 1H) 8.27 (d, J=8.3 Hz, 1H). Melting point:190-191° C. [M+H] calc'd for C₃₁H₄₂F₂N₈O₄ 629. found 629.

Compound 72:(S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-1-N—Boc 3-amino pyrrolidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml).The final compound was purified by reverse phase HPLC and basified togive the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.28 (m, 1H)1.30-1.47 (m, 2H) 1.51-1.72 (m, 4H) 1.73-1.88 (m, 4H) 1.90-2.06 (m, 1H)2.64 (dd, J=11.24, 4.93 Hz, 1H) 2.75 (ddd, J=10.67, 7.89, 6.44 Hz, 1H)2.82-3.03 (m, 2H) 3.31 (s, 3H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H)4.23-4.37 (m, 1H) 4.39-4.53 (m, 1H) 7.44-7.50 (m, 1H) 7.51 (d, J=1.52Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.23 (d, J=7.07 Hz, 1H) 8.26 (d,J=8.34 Hz, 1H). Melting point: 258-263° C. [M+H] calc'd for C₂₆H₃₃F₂N₇O₃530. found 530.

Compound 73:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(pyrrolidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-N—Boc 3-amino pyrrolidine. The final compound waspurified by reverse phase HPLC and basified to give the free base.Further, after washing with water (10 ml), t-butoxycarbonyl (Boc)protection group was removed using 40% TFA in dichloromethane (6 ml).The final compound was purified by reverse phase HPLC and basified togive the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.27 (m, 1H)1.28-1.47 (m, 2H) 1.52-1.71 (m, 4H) 1.71-1.89 (m, 4H) 1.89-2.04 (m, 1H)2.64 (dd, J=11.12, 5.05 Hz, 1H) 2.75 (ddd, J=10.74, 7.96, 6.32 Hz, 1H)2.83-3.03 (m, 2H) 3.31 (s, 3H) 3.94 (s, 3H) 4.06 (t, J=13.52 Hz, 2H)4.22-4.36 (m, 1H) 4.38-4.54 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51(d, J=1.52 Hz, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.23 (d, J=7.07 Hz, 1H)8.26 (d, J=8.34 Hz, 1H). Melting point: 195-198° C. [M+H] calc'd forC₂₆H₃₃F₂N₇O₃ 530. found 530.

Compound 74:(S)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (S)-1-methylpiperidin-3-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.17-1.26 (m, 2H) 1.29-1.46 (m, 3H)1.55-1.73 (m, 5H) 1.75-1.90 (m, 6H) 2.23 (br s, 3H) 2.64-2.78 (m, 1H)2.79-2.95 (m, 1H) 3.31 (s, 3H) 3.90-4.01 (m, 1H) 3.94 (s, 3H) 4.07 (t,J=12.63 Hz, 2H) 4.37-4.53 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51(d, J=1.77 Hz, 1H) 7.91 (s, 1H) 8.10 (d, J=7.33 Hz, 1H) 8.21 (s, 1H)8.27 (d, J=8.34 Hz, 1H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₃ 558. found 558.

Compound 75:(R)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-methylpiperidin-3-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.26 (m, 2H) 1.29-1.46 (m, 3H)1.55-1.73 (m, 5H) 1.75-1.90 (m, 6H) 2.17 (s, 3H) 2.63-2.69 (m, 1H)2.78-2.84 (m, 1H) 3.31 (s, 3H) 3.90-4.01 (m, 1H) 3.94 (s, 3H) 4.06 (t,J=12.63 Hz, 2H) 4.41-4.51 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51(d, J=1.77 Hz, 1H) 7.91 (s, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.21 (s, 1H)8.27 (d, J=8.32 Hz, 1H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₃ 558. found 558.

Compound 76:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-cyclopropyl-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and cyclopropylamine. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.50-0.61 (m, 2H) 0.70 (dd, J=7.07, 2.27 Hz, 2H)1.31-1.48 (m, 2H) 1.51-1.70 (m, 4H) 1.71-1.91 (m, 4H) 2.81 (dt, J=7.14,3.63 Hz, 1H) 3.17 (s, 3H) 3.93 (s, 3H) 4.03 (q, J=7.07 Hz, 2H) 4.46 (t,J=11.62 Hz, 1H) 7.40-7.55 (m, 2H) 7.90 (s, 1H) 8.21 (s, 1H) 8.26 (d,J=8.34 Hz, 1H) 8.37 (d, J=3.79 Hz, 1H). [M+H] C₂₅H₃₀F₂N₆O₃ calc'd for,501. found 501.

Compound 77:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide

Benzyl4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)piperazine-1-carboxylate:The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and benzyl 4-aminopiperazine 1-carboxylate.

4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide:Benzyl4-(4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)piperazine-1-carboxylate(850 mg, 1.25 mmols) was dissolved in ethanol (15 mL), added 10% Pd—C(170 mg, 20% wt) under inert atmosphere and hydrogenated using a balloonfor 8 hrs. Then filtered the solution through celite bed and evaporatedto give the product (630 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.89(m, 10H) 2.70-2.85 (m, 8H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.26Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz, 1H) 7.44 (s, 1H) 7.90 (s, 1H)8.21 (s, 1H) 8.26 (d, J=8.08 Hz, 1H) 9.38 (s, 1H). [M+H] calculated forC₂₆H₃₄F₂N₈O₃, 545. found 545.

Compound 78:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-ethylpiperazin-1-yl)-3-methoxybenzamide

4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide(108 mg, 0.2 mmols), ethyl bromide (33 mg, 0.3 mmols) andN,N-diisopropyl ethylamine (106 μL, 0.3 mmols) were mixed in a screw capvial (5 mL) in DMF (2 mL) heated at 40° C. for 5-8 hrs, then purified toprovide the title compound (76.9 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.99 (t, J=7.1 Hz, 3H) 1.14-1.89 (m, 10H) 2.33 (q, J=6.99 Hz, 2H) 2.48(m, 4H) 2.93 (t, J=4.55 Hz, 4H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t,J=13.22 Hz, 2H) 4.45 (m, 1H). 7.41 (d, J=8.0 Hz, 1H) 7.43 (s, 1H) 7.90(s, 1H) 8.20 (s, 1H) 8.26 (d, J=8.08 Hz, 1H) 9.38 (s, 1H) [M+H]calculated for C₂₈H₃₈F₂N₈O₃, 572. found 572.

Compound 79:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-isopropylpiperazin-1-yl)-3-methoxybenzamide

The title compound was synthesized using a procedure that is analogousto that described in connection with4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-isopropylpiperazin-1-yl)-3-methoxybenzamideexcept that isopropyl bromide. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.98 (d,J=6.32 Hz, 6H) 1.16-1.89 (m, 10H) 2.66 (dt, J=12.95, 6.54 Hz, 1H) 2.53(m, 4H) 2.92 (t, J=4.42 Hz, 4H) 3.31 (s, 3H) 3.94 (s, 3H) 4.06 (t,J=13.26 Hz, 2H) 4.46 (m, 1H). 7.41 (d, J=8.0 Hz, 1H) 7.44 (s, 1H) 7.91(s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H) 9.35 (s, 1H). [M+H]calculated for C₂₉H₄₀F₂N₈O₃, 587. found 587.

Compound 80:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(cyclopropylmethyl)piperazin-1-yl)-3-methoxybenzamidemethoxybenzamide

The title compound was synthesized using a procedure that is analogousto that described in connection with4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-isopropylpiperazin-1-yl)-3-methoxybenzamideexcept that (bromomethyl)cyclopropane. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.08 (q, J=4.88 Hz, 2H) 0.38-0.58 (m, 2H) 0.70-0.93 (m, 1H) 1.14-1.89(m, 10H) 2.19 (d, J=6.32 Hz, 2H) 2.52 (m, 4H) 2.95 (m, 4H) 3.31 (s, 3H)3.94 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz,1H) 7.44 (s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H) 9.39(s, 1H). [M+H] calculated for C₃₀H₄₀F₂N₈O₃, 599. found 599.

Compound 81:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(4-(2-(dimethylamino)acetyl)piperazin-1-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamideusing a procedure that is analogous to that described in connection withamide formation except that N,N-dimethylglycine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.12-1.89 (m, 10H) 2.19 (s, 6H) 2.89 (br. s., 2H) 2.94(br. s., 2H) 3.31 (s, 3H) 3.54 (br. s., 2H) 3.63 (br. s., 2H) 3.93 (s,3H) 4.06 (t, J=13.39 Hz, 2H) 4.46 (m, 1H) 7.42 (d, J=8.0 Hz, 1H) 7.44(s, 1H) 7.91 (s, 1H) 8.21 (s, 1H) 8.28 (d, J=8.33 Hz, 1H) 9.52 (s, 1H).[M+H] calculated for C₃₀H₄₁F₂N₉O₄, 630. found 630.

Compound 82:4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid

Ethyl4-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-3,3-difluoro-2-oxobutanoate:Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-2,2-difluoropropanoatewas obtained through reductive amination of ethyl4-amino-3,3-difluoro-2-oxobutanoate and (R)-3-methylcyclopentanone. Theresulting product was further reacted with 2,4-dichloronitropyrimidineto yield ethyl4-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-3,3-difluoro-2-oxobutanoate.The product crashed out and was collected. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.87-1.03 (m, 3H) 1.16-1.34 (m, 4H) 1.47-2.18 (m, 6H) 3.62-3.81 (m,1H) 4.25 (q, J=7.07 Hz, 4H) 8.94 (s, 1H). m/z 393.

2-chloro-7,7-difluoro-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:Compound ethyl4-((2-chloro-5-nitropyrimidin-4-yl)((3R)-3-methylcyclopentyl)amino)-3,3-difluoro-2-oxobutanoatewas dissolved in AcOH and then cooled in an ice bath (sometimes thiscrystallizes out upon cooling). Iron powder (2 equivalents) was addedfollowed by the slow addition of HCl (15 mL, conc.). After 10 minutesthe reaction was transferred to a heat bath and left to stir at 60° C.for 5 hours. The reaction was then cooled, the stir bar and unreactediron removed with a magnet (or by filtration through paper), and thesolvent volume reduced by about 75% on a rotovap. The mixture was thendiluted with ice water (150 mL) and EtOAc (1500 mL), the layersseparated, the aqueous layer washed with EtOAc (2×150 mL), the organicextracts combined, washed with sat. NaHCO₃ (100 mL), brine (100 mL),dried over MgSO₄, filtered and concentrated to yield a brown syrup.Trituration with EtOAc (15 mL) and ether (100 mL) to coax out a tannishsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-2.29 (m, 10H) 3.80-4.20 (m,2H) 4.81-5.07 (m, 1H) 8.12 (s, 1H) 11.07 (br. s., 1H). m/z 317.

2-chloro-7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:2-Chloro-7,7-difluoro-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-onewas methylated on 5-position using sodium hydride and methyl iodide.After 30 minutes the reaction was deemed complete by LCMS, poured intoice, the solution acidified with 1N HCl, the product filtered off as atan solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-2.22 (m, 10H) 3.34 (s,3H) 4.04-4.35 (m, 2H) 4.72-5.04 (m, 1H) 8.35 (s, 1H). m/z 331.2 (M+H)⁺.

4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid:2-Chloro-7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(500 mg, 1.51 mmol) and 4-amino-3-methoxybenzoic acid (316.0 mg, 1.89mmol) were weighed into a flask. 4-Methylbenzenesulfonic acidmonohydrate (230.0 mg, 1.21 mmol) was weighed into a separate flask anddissolved in dioxane (15 ml). The toxic acid solution was then added tothe flask containing the two starting materials. The reaction wasstirred at 85° C. for 48 hours followed by 100° C. for an additional 48hours. The dark brown mixture was cooled to room temperature andfiltered through paper. The solids were washed with ethyl acetate (15ml). m/z 462.4 (M+H)⁺.

Compound 83:4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

To a mixture of the4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid, 1-methylpiperidin-4-amine (1.1 equivalent) and DIEA (3-6equivalent) in 20 mL of anhydrous DMF, was added HATU (1.5 to 2equivalent). The reaction mixture was stirred for 30 min. The reactionmixture was then diluted with ethyl acetate, washed with water andbrine. The organic layer dried over Na₂SO₄ followed by HPLCpurification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96-1.06 (m, 3H)1.06-2.12 (m, 13H) 2.16 (s, 3H) 2.77 (d, J=11.87 Hz, 2H) 3.32 (br. s.,3H) 3.65-3.80 (m, 1H) 3.93 (s, 3H) 3.97-4.12 (m, 2H) 4.73-4.96 (m, 1H)7.44-7.52 (m, 2H) 7.97 (d, J=6.06 Hz, 1H) 8.12 (d, J=7.83 Hz, 1H) 8.25(d, 2H). [M+H] calc'd for C₂₈H₃₇F₂N₇O₃ 558. found 558.

Compound 84:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized using an analogous procedure to thatdescribed in connection with Compound 3 except that2-fluoro-beta-alaninate was used as the starting material. The finalproduct was purified on reversed phase HPLC as TFA salt. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.55-1.87 (m, 11H) 1.91-2.08 (m, 3H) 2.18 (s, 3H)2.79 (d, J=11.4 Hz, 2H) 3.24 (s, 3H) 3.61-3.83 (m, 3H) 3.94 (s, 3H) 4.77(quin., J=8.3 Hz, 1H) 5.52 (qd, 1H) 7.47 (dd, J=1.8 Hz, 1H) 7.49 (s, 1H)7.86 (s, 1H) 8.11 (d, J=7.8 Hz, 1H) 8.16 (s, 1H) 8.33 (d, J=8.34 Hz,1H). [M+H] calc'd for C₂₇H₃₆FN₇O₃ 526. found 526.

Compound 85:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized using the analogous procedure to thatdescribed in connection with Compound 3 except that2-(aminomethyl)-2,3,3,3-tetrafluoropropanoic acid was used as thestarting material. The final product was purified on reversed phase HPLCas TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.76 (m, 10H)1.83-2.09 (m, 4H) 2.19 (s, 3H) 2.80 (d, J=11.9 Hz, 2H) 3.32 (s, 3H)3.69-3.81 (m, 1H) 3.89 (t, 1H) 3.94 (s, 3H) 4.15-4.35 (q, 1H) 4.72(quin., J=8.1 Hz, 1H) 7.48 (dd, J=1.77 Hz, 1H) 7.50 (s, 1H) 8.00 (s, 1H)8.10 (d, J=7.8 Hz, 1H) 8.26 (d, J=8.3 Hz, 1H) 8.32 (s, 1H). [M+H] calc'dfor C₂₈H₃₅F₄N₇O₃ 594. found 594.

Compound 86:4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Ethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate: A mixture ofmethyl 2-methylglycidate (3.18 g, 27 mmol) and cyclopentylamine (4 mL,41 mmol) in ethanol (50 mL) was heated at 80° C. for 3 d. The reactionmixture was then concentrated, diluted to EtOAc, washed by NaHCO₃, brineand water. Organic layer was dried, concentrated to give a residue whichis used for next step without further purification (3.9 g, 60%). [M+H]calc'd for C₁₁H₂₁NO₃, 216. found 216.

Ethyl 3-(benzyl(cyclopentyl)amino)-2-hydroxy-2-methylpropanoate: Toethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate (3.9 g, 18 mmol)in 50 ml of acetonitrile at room temperature, was added benzyl bromide(3.2 ml, 27.2 mmol) dropwise, followed by K₂CO₃ (7.5 g, 54.3 mmol). Thereaction mixture was heated at 80° C. for 18 h. It was then diluted toEtOAc, washed by brine and water. Organic extract dried and concentratedto a residue, which was purified on silica gel columnchromatographically (Hex/EtOAc=100:1 to 10:1) to give 4.2 g product(77%). [M+H] calc'd for C₁₈H₂₇NO₃, 306. found 306.

Ethyl 3-(benzyl(cyclopentyl)amino)-2-fluoro-2-methylpropanoate: To ethyl3-(benzyl(cyclopentyl)amino)-2-hydroxy-2-methylpropanoate (4.2 g, 14mmol) in 50 ml of dichlormethane at −78° C., was added DAST (2.7 ml, 21mmol) dropwise. The reaction mixture was gradually warmed up to roomtemperature and stirred for 2 h. It was then diluted to dichloromethane,washed by NaHCO₃, brine and water. Organic extract dried andconcentrated to a residue, which was purified on silica gel columnchromatographically (Hex/EtOAc=40:1 to 20:1) to give 3.5 g product (83%)as light yellow liquid. [M+H] calc'd for C₁₈H₂₆FNO₂, 308. found 308.

Ethyl 3-(cyclopentylamino)-2-fluoro-2-methylpropanoate: A solution ofethyl 3-(benzyl(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.5 g,11.4 mmol) in ethanol (30 mL) was hydrogenated with Pd(OH)₂ (20%, 400mg, 0.57 mmol) in presence of TFA (11.4 mmol) at atmospheric pressurefor 20 h. The reaction mixture was filtered through celite. The filtratewas concentrated and diluted to EtOAc/H₂O, aqueous layer was basified topH=11-12 by 1N NaOH. The organic layer was then dried and concentratedto give the product (2.1 g, 85%) as light yellow liquid. [M+H] calc'dfor C₁₁H₂₀FNO₂, 218. found 218.

Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2-fluoro-2-methylpropanoate:To a solution of 2,4-dichloro-5-nitropyrimidine (2.14 g, 11.0 mmol) inanhydrous acetone (30 ml) at 0° C., was added dropwise a solution ofcompound ethyl 3-(cyclopentylamino)-2-fluoro-2-methylpropanoate (2 g,9.22 mmol) in acetone (10 mL) over 10 min. After which, potassiumcarbonate (3.8 g, 27.7 mmol) was added and the whole was stirred at rtfor 18 h. After evaporation in vacuo, the residue was partitionedbetween ethyl acetate (200 ml) and water (200 ml). The organic layer waswashed with NaHCO₃, brine and water, dried over Na₂SO₄ and concentratedin vacuo to give a red residue which was used directly for next step.[M+H] calc'd for C₁₅H₂₀ClFN₄O₄, 375. found 375.

2-Chloro-9-cyclopentyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a suspension of ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2-fluoro-2-methylpropanoate(3.4 g, 9 mmol), reduced iron (1.2 g, 23 mmol) in acetic acid (20 ml)was added dropwise concentrated hydrochloric acid (2 ml) at 0° C. Thereaction mixture was stirred at 60° C. for 18 h. It was thenconcentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solutionat 0° C. The whole was filtered through celite, washed with EtOAc. Thefiltrate was then separated. The organic layer was dried over Na₂SO₄.The solution was concentrated in vacuo followed by precipitation fromether to afford the product (620 mg, 23% yield) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.42-1.67 (m, 7H) 1.72 (d, J=4.0 Hz, 2H)1.77-1.91 (m, 2H) 3.58-3.77 (m, 2H) 5.01 (t, J=8.2 Hz, 1H) 7.97 (s, 1H)10.36 (s, 1H). [M+H] calc'd for C₁₃H₁₆ClFN₄O, 299. found 299.

2-Chloro-9-cyclopentyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a solution of2-chloro-9-cyclopentyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(3 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion inmineral oil, 124 mg, 3.1 mmol) at 0° C., followed by the dropwiseaddition of methyl iodide (0.193 mL, 3.1 mmol). The reaction mixture waswarmed up to rt and stirred for 1 h. The whole was poured intoice-water, extracted with ethyl acetate. The organic layer was washedwith brine and dried over Na₂SO₄. The solution was concentrated in vacuoand used for next step reaction. [M+H] calc'd for C₁₄H₁₈ClFN₄O, 313.found 313.

4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid: A mixture of2-chloro-9-cyclopentyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(obtained above), 4-amino-3-methoxybenzoic acid (585 mg, 3.5 mmol),isopropanol (10 ml), water (5 mL) and concentrated hydrochloric acid (10drops) was stirred at 100° C. for 20 h. Solid was filtered to give theproduct as white solid (396 mg). [M+H] calc'd for C₂₂H₂₆FN₅O₄, 444.found 444.

Compound 87:4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid and 1-methylpiperidin-4-amine as described in the General procedurefor amide bond synthesis using HATU. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.41-1.65 (m, 6H) 1.65-1.86 (m, 6H) 1.93 (d, J=3.3 Hz,1H) 2.07 (s, 1H) 2.04 (d, J=13.1 Hz, 1H) 2.81 (d, J=5.1 Hz, 1H) 2.78 (d,J=4.6 Hz, 3H) 2.99-3.17 (m, 2H) 3.27 (s, 4H) 3.48 (d, J=11.6 Hz, 2H)4.83 (t, J=7.8 Hz, 1H) 7.53 (dd, J=8.3, 1.8 Hz, 1H) 7.55 (s, 1H) 8.08(d, J=8.3 Hz, 1H) 8.17 (s, 1H) 8.43 (d, J=7.3 Hz, 1H) 8.98 (br. s., 1H)9.54 (br. s., 1H). [M+H] calc'd for C₂₈H₃₈FN₇O₃, 540. found 540.

Compound 88:4-(9-Cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.65 (m, 5H) 1.65-1.88(m, 4H) 1.88-2.01 (m, 1H) 2.92 (dd, J=4.7, 2.4 Hz, 3H) 3.28 (s, 3H) 3.95(s, 3H) 4.01-4.25 (m, 2H) 4.31-4.55 (m, 2H) 4.64-4.89 (m, 2H) 7.44-7.63(m, 2H) 8.21 (d, J=8.3 Hz, 1H) 8.18 (s, 1H) 8.97-9.09 (m, 1H) 9.78 (br.s., 1H). [M+H] calc'd for C₂₆H₃₄FN₇O₃, 512. found 512.

Compound 89:4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Ethyl 3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate: A mixture ofmethyl 2-methylglycidate (3.2 mL, 30 mmol) and cyclohexylamine (5.2 mL,45 mmol) in ethanol (50 mL) was heated at 80° C. for 24 h. The reactionmixture was then concentrated, diluted to EtOAc, washed by NaHCO₃, brineand water. Organic layer was dried, concentrated to give a residue whichis used for next step without further purification (6.7 g, 97%). [M+H]calc'd for C₁₂H₂₃NO₃, 230. found 230.

Ethyl 3-(benzyl(cyclohexyl)amino)-2-hydroxy-2-methylpropanoate: To ethyl3-(cyclohexylamino)-2-hydroxy-2-methylpropanoate (6.7 g, 29.2 mmol) in50 ml of acetonitrile at room temperature, was added benzyl bromide (5.2ml, 43.8 mmol) dropwise, followed by K₂CO₃ (12 g, 87.6 mmol). Thereaction mixture was heated at 80° C. for 18 h. It was then diluted toEtOAc, washed by brine and water. Organic extract dried and concentratedto a residue, which was purified on silica gel columnchromatographically (Hex/EtOAc=100:1 to 10:1) to give 7 g product (75%).[M+H] calc'd for C₁₉H₂₉NO₃, 320. found 320.

Ethyl 3-(benzyl(cyclohexyl)amino)-2-fluoro-2-methylpropanoate: To ethyl3-(benzyl(cyclohexyl)amino)-2-hydroxy-2-methylpropanoate (7 g, 21.9mmol) in 50 ml of dichlormethane at −78° C., was added DAST (4.3 ml,32.8 mmol) dropwise. The reaction mixture was gradually warmed up toroom temperature and stirred for 2 h. It was then diluted todichloromethane, washed by NaHCO₃, brine and water. Organic extractdried and concentrated to a residue, which was purified on silica gelcolumn chromatographically (Hex/EtOAc=40:1 to 20:1) to give 6.8 gproduct (97%) as light yellow liquid. [M+H] calc'd for C₁₉H₂₈FNO₂, 322.found 322.

Ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate: A solution ofethyl 3-(benzyl(cyclohexyl)amino)-2-fluoro-2-methylpropanoate (1.6 g, 5mmol) in ethanol (20 mL) was hydrogenated with Pd(OH)₂ (20%, 176 mg,0.25 mmol) in presence of TFA (5 mmol) at atmospheric pressure for 20 h.The reaction mixture was filtered through celite. The filtrate wasconcentrated and diluted to EtOAc/H₂O, aqueous layer was basified topH=11-12 by 1N NaOH. The organic layer was then dried and concentratedto give the product (1.1 g, 95%) as light yellow liquid. [M+H] calc'dfor C₁₂H₂₂FNO₂, 232. found 232.

Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-2-fluoro-2-methylpropanoate:To a solution of 2,4-dichloro-5-nitropyrimidine (970 mg, 5 mmol) inanhydrous acetone (20 ml) at 0° C., was added dropwise a solution ofethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate (1.1 g, 4.76 mmol)in acetone (5 mL) over 10 min. After which, potassium carbonate (1.66 g,12 mmol) was added and the whole was stirred at rt for 18 h. Afterevaporation in vacuo, the residue was partitioned between ethyl acetate(200 ml) and water (200 ml). The organic layer was washed with NaHCO₃,brine and water, dried over Na₂SO₄ and concentrated in vacuo to give ared residue (1.9 g) which was used directly for next step. [M+H] calc'dfor C₁₆H₂₂ClFN₄O₄, 389. found 389.

2-Chloro-9-cyclohexyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a suspension of ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclohexyl)amino)-2-fluoro-2-methylpropanoate(1.9 g, 4.76 mmol), reduced iron (0.66 g, 12 mmol) in acetic acid (20ml) was added dropwise concentrated hydrochloric acid (2 ml) at 0° C.The reaction mixture was stirred at 60° C. for 18 h. It was thenconcentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solutionat 0° C. The whole was filtered through celite, washed with EtOAc. Thefiltrate was then separated. The organic layer was dried over Na₂SO₄.The solution was concentrated in vacuo followed by precipitation fromether to afford compound X (780 mg, 52% yield) as white solid. [M+H]calc'd for C₁₄H₁₈ClFN₄O, 313. found 313.

2-Chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a solution of2-chloro-9-cyclohexyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(313 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60%dispersion in mineral oil, 44 mg, 1.1 mmol) at 0° C., followed by thedropwise addition of methyl iodide (0.07 mL, 1.1 mmol). The reactionmixture was warmed up to rt and stirred for 1 h. The whole was pouredinto ice-water, extracted with ethyl acetate. The organic layer waswashed with brine and dried over Na₂SO₄. The solution was concentratedin vacuo and used for next step reaction (330 mg). [M+H] calc'd forC₁₅H₂₀ClFN₄O, 327. found 327.

4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid: A mixture of2-chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(330 mg, 1 mmol), 4-amino-3-methoxybenzoic acid (184 mg, 1.1 mmol),isopropanol (10 ml), and concentrated hydrochloric acid (10 drops) wasstirred at 100° C. for 20 h. Solid was filtered to give 146 mg productas white solid (32%). [M+H] calc'd for C₂₃H₂₈FN₅O₄, 458. found 458.

4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide:The title compound was synthesized using an analogous procedure to thatdescribed in connection with Compound 87 except that ethyl3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commerciallyavailable starting material methyl 2-methyloxirane-2-carboxylate, wasused and the final compound was purified by reverse phase HPLC andbasified to give the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.04-1.36 (m, 2H) 1.28-2.08 (m, 17H) 2.19 (s, 3H) 2.81 (d, J=10.6 Hz,2H) 3.26 (s, 3H) 3.60-3.85 (m, 3H) 3.95 (s, 3H) 4.45 (m, 1H) 7.47 (d,J=8.3 Hz, 1H) 7.50 (s, 1H) 7.75 (s, 1H) 7.97-8.20 (m, 2H) 8.32 (d, J=8.3Hz, 1H). [M+H] calc'd for C₂₉H₄₀FN₇O₃, 554. found 554.

Compound 90:4-(9-Cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (m, 2H) 1.62-2.06 (m,14H), 2.29 (s, 1H) 2.50 (s, 3H) 3.25 (t, J=6.3 Hz, 2H) 3.47 (s, 3H) 3.80(t, J=6.6 Hz, 2H) 3.88-4.09 (m, 2H) 4.16 (s, 3H) 4.52-4.77 (m, 1H) 7.70(d, J=8.3 Hz, 1H) 8.00 (s, 1H). [M+H] calc'd for C₂₇H₃₆FN₇O₃, 526. found526.

Compound 91:(R)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

2-Methylenebutanoic acid: The ethyl malonic acid (25.8 g, 195 mmol) wasdissolved in 200 mL water, and 37% formaldehyde (15 mL, 200 mmol) anddiethylamine (2M in THF, 100 mL, 200 mmol) were added. The reactionmixture was stirred at room temperature for 20 h and then refluxed at80° C. for 5 h. It was then cooled down to room temperature, acidifiedby concentrated HCl, extracted with dicholoromethane (3×200 mL). Theorganic extracts combined, dried over Na₂SO₄ and concentrated to givethe product as clear liquid (14 g, 72%). ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.12 (t, J=7.4 Hz, 3H) 2.35 (q, J=7.3 Hz, 2H) 5.66 (s, 1H) 6.30(s, 1H).

Methyl 2-methylenebutanoate: A mixture of 2-methylenebutanoic acid (14g, 140 mmol), methane sulfonic acid (40 drops) in dichloromethane (200mL) and methanol (50 mL) was refluxed at 80° C. for 3 d. It was thencooled to room temperature, washed by NaHCO₃. Organic extract was thendried over Na₂SO₄, concentrated at low vacuum and low temp. (<20° C.) togive the product as clear liquid (quantitative yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.08 (t, J=7.3 Hz, 3H) 2.33 (q, J=7.3 Hz, 2H) 3.76(s, 3H) 5.53 (d, J=1.5 Hz, 1H) 6.13 (d, J=1.0 Hz, 1H).

Methyl 2-ethyloxirane-2-carboxylate: A mixture of methyl2-methylenebutanoate (140 mmol), mCPBA (77%, 67 g, 300 mmol) and4,4′-thiobis(2-tert-butyl-6-methylphenol) (250 mg, 0.7 mmol) in 100 mlof dry 1,2-dichloroethane was refluxed at 80° C. for 2 d. It was thencooled down, solid filtered. Filtrate washed by Na₂SO₃, NaHCO₃, brineand water until clear. It was then concentrated to a light yellow liquid(7.5 g, 41%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (td, J=7.4, 1.3Hz, 3H) 1.78 (dq, J=14.6, 7.3 Hz, 1H) 2.10 (dq, J=15.4, 7.6 Hz, 1H) 2.80(dd, J=5.8, 1.0 Hz, 1H) 3.05 (dd, J=5.8, 1.0 Hz, 1H) 3.77 (d, J=1.5 Hz,3H).

Ethyl 2-((cyclopentylamino)methyl)-2-hydroxybutanoate: A mixture ofmethyl 2-ethyloxirane-2-carboxylate (1.9 g, 15 mmol) andcyclopentylamine (2.2 mL, 22 mmol) in ethanol (50 mL) was heated at 80°C. for 3 d. The reaction mixture was then concentrated, diluted toEtOAc, washed by NaHCO₃, brine and water. Organic layer was dried,concentrated to give a residue which is used for next step withoutfurther purification (2.7 g, 80%). [M+H] calc'd for C₁₂H₂₃NO₃, 230.found 230.

Ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-hydroxybutanoate: To ethyl2-((cyclopentylamino)methyl)-2-hydroxybutanoate (2.7 g, 12 mmol) in 50ml of acetonitrile at room temperature, was added benzyl bromide (2.1ml, 18 mmol) dropwise, followed by K₂CO₃ (5 g, 35 mmol). The reactionmixture was heated at 80° C. for 18 h. It was then diluted to EtOAc,washed by brine and water. Organic extract dried and concentrated to aresidue, which was purified on silica gel column chromatographically(Hex/EtOAc=100:1 to 4:1) to give 2.9 g product (77%). [M+H] calc'd forC₁₉H₂₉NO₃, 320. found 320.

Ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-fluorobutanoate: To ethyl2-((benzyl(cyclopentyl)amino)methyl)-2-hydroxybutanoate (2.9 g, 9.1mmol) in 30 ml of dichlormethane at −78° C., was added DAST (2.4 ml, 18mmol) dropwise. The reaction mixture was gradually warmed up to roomtemperature and stirred for 1 h. It was then diluted to dichloromethane,washed by NaHCO₃, brine and water. Organic extract dried andconcentrated to a residue, which was purified on silica gel columnchromatographically (Hex/EtOAc=40:1 to 20:1) to give 2.2 g product (75%)as light yellow liquid. [M+H] calc'd for C₁₉H₂₈FNO₂, 322. found 322.

Ethyl 2-((cyclopentylamino)methyl)-2-fluorobutanoate: A solution ofethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-fluorobutanoate (2.2 g, 6.8mmol) in ethanol (20 mL) was hydrogenated with Pd(OH)₂ (20%, 240 mg,0.34 mmol) in presence of TFA (6.8 mmol) at atmospheric pressure for 20h. The reaction mixture was filtered through celite. The filtrate wasconcentrated and diluted to EtOAc/H₂O, aqueous layer was basified topH=11-12 by 1N NaOH. The organic layer was then dried and concentratedto give the product (1.38 g, 88%) as light yellow liquid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 0.95 (t, J=7.6 Hz, 3H) 1.31 (t, J=7.1 Hz, 4H)1.41-1.94 (m, 9H) 2.88-3.08 (m, 3H) 4.26 (qd, J=7.12, 2.40 Hz, 2H).[M+H] calc'd for C₁₂H₂₂FNO₂, 232. found 232.

Ethyl2-(((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)methyl)-2-fluorobutanoate:To a solution of 2,4-dichloro-5-nitropyrimidine (1.4 g, 7.2 mmol) inanhydrous acetone (50 ml) at 0° C., was added dropwise a solution ofethyl 2-((cyclopentylamino)methyl)-2-fluorobutanoate (1.38 g, 6 mmol) inacetone (10 mL) over 10 min. After which, potassium carbonate (2.5 g, 18mmol) was added and the whole was stirred at rt for 18 h. Afterevaporation in vacuo, the residue was partitioned between ethyl acetate(200 ml) and water (200 ml). The organic layer was washed with NaHCO₃,brine and water, dried over Na₂SO₄ and concentrated in vacuo to give ared residue which was used directly for next step (2.6 g). [M+H] calc'dfor C₁₆H₂₂ClFN₄O₄, 389. found 389.

2-Chloro-9-cyclopentyl-7-ethyl-7-fluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a suspension of ethyl2-(((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)methyl)-2-fluorobutanoate(2.6 g, 6 mmol), reduced iron (840 mg, 15 mmol) in acetic acid (20 ml)was added dropwise concentrated hydrochloric acid (2 ml) at 0° C. Thereaction mixture was stirred at 60° C. for 18 h. It was thenconcentrated in vacuo, diluted to EtOAc, basified with 10% NaOH solutionat 0° C. The whole was filtered through celite, washed with EtOAc. Thefiltrate was then separated. The organic layer was dried over Na₂SO₄.The solution was concentrated in vacuo followed by precipitation fromether to afford the product (0.9 g, 48% yield) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.90 (t, J=7.3 Hz, 3H) 1.53-1.91 (m, 10H)3.53-3.69 (m, 1H) 3.78 (d, J=13.4 Hz, 1H) 5.05 (t, J=8.5 Hz, 1H) 7.96(s, 1H) 10.31 (d, J=1.5 Hz, 1H). [M+H] calc'd for C₁₄H₁₈ClFN₄O, 313.found 313.

2-Chloro-9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:To a solution of2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(890 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60%dispersion in mineral oil, 116 mg, 2.9 mmol) at 0° C., followed by thedropwise addition of methyl iodide (0.18 mL, 2.9 mmol). The reactionmixture was warmed up to rt and stirred for 1 h. The whole was pouredinto ice-water, extracted with ethyl acetate. The organic layer waswashed with brine and dried over Na₂SO₄. The solution was concentratedin vacuo followed by precipitation from ether/EtOA to afford the product(750 mg, 80% yield) as light tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.90 (t, J=7.3 Hz, 3H) 1.55-1.98 (m, 10H) 3.28 (s, 3H) 3.70-3.93 (m, 2H)4.74 (t, J=7.9 Hz, 1H) 8.25 (s, 1H). [M+H] calc'd for C₁₅H₂₀ClFN₄O, 327.found 327.

4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid: A mixture of2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(630 mg, 1.93 mmol), 4-amino-3-methoxybenzoic acid (484 mg, 2.9 mmol),isopropanol (20 ml), and concentrated hydrochloric acid (10 drops) wasstirred at 100° C. for 20 h. Solid was filtered to give 730 mg productas white solid (83%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (t, J=7.3 Hz,3H) 1.56 (br. s., 3H) 1.67-1.96 (m, 6H) 3.28 (s, 3H) 3.74-3.92 (m, 3H)3.94 (s, 3H) 4.91 (t, J=7.8 Hz, 1H) 7.21-7.43 (m, 1H) 7.47-7.69 (m, 2H)8.13 (d, J=8.1 Hz, 1H) 8.24 (s, 1H) 9.32 (br. s., 1H). [M+H] calc'd forC₂₃H₂₈FN₅O₄, 458. found 458.

Compound 92:4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and. 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J=7.3 Hz, 3H) 1.60-1.75 (m, 11H)1.84-2.09 (m, 5H) 2.19 (s, 3H) 2.80 (d, J=11.1 Hz, 2H) 3.26 (s, 3H)3.60-3.83 (m, 3H) 3.94 (s, 3H) 4.78 (t, J=8.1 Hz, 1H) 7.35-7.60 (m, 2H)7.80 (s, 1H) 8.08 (d, J=7.6 Hz, 1H) 8.16 (s, 1H) 8.32 (d, J=8.3 Hz, 1H).Melting point: 149-153° C. [M+H] calc'd for C₂₉H₄₀FN₇O₃, 554. found 554.

Compound 93: (R) and(S)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The enantiomers of4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamidewere separated using SFC (ChiralPak OD-H in supercritical CO₂). Theabsolute configuration was determined using co-crystal of the titlecompound and PLK1 enzyme. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (t,J=7.33 Hz, 3H), 1.58-1.82 (m, 9H), 1.85-2.14 (m, 5H), 2.22 (t, J=10.86Hz, 2H), 2.35 (s, 3H), 2.90 (d, J=12.13 Hz, 2H), 3.37 (s, 3H), 3.58-3.82(m, 2H), 3.95-4.08 (m, 4H), 4.84-4.99 (m, 1H), 5.97 (d, J=7.83 Hz, 1H),7.24 (dd, J=8.46, 1.89 Hz, 1H), 7.43 (d, J=1.77 Hz, 1H), 7.70 (s, 1H),7.98 (s, 1H), 8.49 (d, J=8.34 Hz, 1H) [M+H] calc'd for C₂₉H₄₀FN₇O₃ 554.found 554.

Compound 94: (R) and(S)-4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The enantiomers of4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamidewere separated using SFC (ChiralPak OD-H in supercritical CO₂). ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 0.99 (t, J=7.33 Hz, 3H), 1.58-1.82 (m,9H), 1.85-2.14 (m, 5H), 2.22 (t, J=10.86 Hz, 2H), 2.35 (s, 3H), 2.90 (d,J=12.13 Hz, 2H), 3.37 (s, 3H), 3.58-3.82 (m, 2H), 3.95-4.08 (m, 4H),4.84-4.99 (m, 1H), 5.97 (d, J=7.83 Hz, 1H), 7.24 (dd, J=8.46, 1.89 Hz,1H), 7.43 (d, J=1.77 Hz, 1H), 7.70 (s, 1H), 7.98 (s, 1H), 8.49 (d,J=8.34 Hz, 1H) [M+H] calc'd for C₂₉H₄₀FN₇O₃ 554. found 554.

Compound 95:4-(9-Cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J=7.3 Hz, 3H)1.6-1.87 (m, 7H) 1.89-1.99 (m, 3H) 2.29 (s, 3H) 3.04 (t, J=7.1 Hz, 2H)3.27 (s, 3H) 3.59 (t, J=7.2 Hz, 2H) 3.64-3.87 (m, 2H) 3.95 (s, 3H)4.29-4.53 (m, 1H) 4.79 (t, J=8.1 Hz, 1H) 7.42-7.59 (m, 2H) 7.82 (s, 1H)8.17 (s, 1H) 8.34 (d, J=8.3 Hz, 1H) 8.61 (d, J=6.8 Hz, 1H). [M+H] calc'dfor C₂₇H₃₆FN₇O₃, 526. found 526.

Compound 96:4-(9-Cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and. 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J=7.4 Hz, 3H) 1.08-2.06 (m, 16H)2.20 (s, 3H) 2.82 (d, J=11.1 Hz, 2H) 3.25 (s, 4H) 3.60-3.85 (m, 3H) 3.95(s, 3H) 4.49 (m, 1H) 7.47 (d, J=8.3 Hz, 1H) 7.50 (s, 1H) 7.77 (s, 1H)8.01-8.19 (m, 2H) 8.31 (d, J=8.3 Hz, 1H). [M+H] calc'd for C₃₀H₄₂FN₇O₃,568. found 568.

Compound 97:4-(9-Cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine hydrochloride. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-0.95 (m, 1H) 0.89 (t,J=7.3 Hz, 3H) 1.07-1.92 (m, 12H) 2.29 (s, 3H) 3.03 (t, J=7.1 Hz, 2H)3.26 (s, 3H) 3.51-3.76 (m, 1H) 3.58 (t, J=7.2 Hz, 2H) 3.76-3.87 (m, 1H)3.95 (s, 3H) 4.44 (m, 1H) 7.49 (d, J=8.3 Hz, 1H) 7.52 (s, 1H) 7.78 (s,1H) 8.11 (s, 1H) 8.33 (d, J=8.6 Hz, 1H) 8.63 (d, J=6.8 Hz, 1H). [M+H]calc'd for C₂₈H₃₈FN₇O₃, 540. found 540.

Compound 98:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid

2-Chloro-9-cyclopentyl-7-(1-hydroxyethyl)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:In a round bottom flask,2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(0.840 g, 3.0 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooledto −78° C., then added 2.0 M lithium diisopropyl amide intetrahydrofuran (6.0 mmol) drop wise. After 30 minutes, acetaldehyde(1.056 g, 24.0 mmol) in 6.0 mL tetrahydrofuran was added slowly dropwise to it, continued stirring for 60 minutes. After disappearing thestarting material, cooled the reaction flask to −78° C., then quenchedwith sat. ammonium chloride solution (3 mL). At room temperature, theresultant reaction mixture was taken into ethyl acetate (50 mL), washedwith 0.1 N HCl, ammonium chloride solution and finally with water, driedover sodium sulphate and evaporated. Purified the product using columnchromatography with hexane:ethyl acetate mixtures to give the product(0.842 g, 86%). [M+H] calculated for C₁₅H₂₁ClN₄O₂, 325. found 325.

2-Chloro-9-cyclopentyl-7-ethylidene-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:In a round bottom flask,2-chloro-9-cyclopentyl-7-(1-hydroxyethyl)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(1.60 g, 4.94 mmol) was dissolved in dichloromethane (15 mL) and cooledto 0° C. Then added triethylamine (1.39 mL, 9.88 mmol) to it, after 5minutes added methanesulfonyl chloride (0.46 mL, 5.93 mmol) drop wise,continued stirring at room temperature for 14 hrs. Then aftercompletion, the reaction mixture was taken into dichloromethane, washedwith ice cold water (50 mL), dried over sodium sulfate and evaporated.The resultant O-methane sulfonyl compound was dissolved in drytetrahydrofuran and cooled to 0° C., and then added 60% sodium hydridein mineral oil (0.218 g, 5.47 mmol) portion wise slowly, continued atroom temperature for another 30 minutes. After completing the reaction,the reaction mixture was slowly added to ice cold water (50 mL) andextracted with ethyl acetate (2×50 mL), ethyl acetate layer was driedevaporated and purified using column chromatography to yield compound23-2 (1.38 g, 94%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12 (d, J=6.06 Hz,3H) 1.42-2.10 (m, 8H) 3.18 (s, 3H) 3.42-4.05 (m, 3H) 4.75 (d, J=6.06 Hz,1H) 4.85 (quin, J=8.39 Hz, 1H) 8.06-8.23 (m, 1H). [M+H] calculated forC₁₅H₁₉ClN₄O, 307. found 307.

2-Chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:2-Chloro-9-cyclopentyl-7-ethylidene-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(1.01 g, 3.30 mmol) in dry tetrahydrofuran (10 mL) was added to 1:1molar 2 M lithium diisopropyl amide in tetrahydrofuran and hexamethylphosphoramide (HMPA) (3.96 mmol each) in tetrahydrofuran (5 mL) at −78°C. After 20 minutes, N-fluorobenzene sulfonimide (2.46 mmol) was addeddropwise to it. Continued the reaction at −78° C. for 30 minutes, andthen elevated the temperature to 0° C. for 30 minutes. Afterdisappearing the starting material, cooled the reaction flask to −78°C., then quenched with sat. ammonium chloride solution (6 mL). At roomtemperature, the resultant reaction mixture was taken into ethyl acetate(70 mL), washed with ammonium chloride solution and finally with water,dried over sodium sulphate and evaporated. Purified the product usingcolumn chromatography with hexane:ethyl acetate mixtures to give theproduct. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53-2.10 (m, 8H) 3.38 (s,3H) 3.63-3.88 (m, 1H) 4.12 (m, 1H) 4.96 (quin, J=8.59 Hz, 1H) 5.41 (d,J=11.12 Hz, 1H) 5.49 (dd, J=17.18, 2.02 Hz, 1H) 6.02 (ddd, J=17.37,14.72, 10.86 Hz, 1H) 7.97 (s, 1H). [M+H] calculated for C₁₅H₁₈ClFN₄O,325. found 325.

4-(9-Cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid:2-Chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one,4-amino-3-methoxy benzoic acid (1.2 equivalent), i-PrOH and conc. HCl(30 drops) were heated to 95° C. for 18 hours. A this time the reactionwas cooled to room temperature and filtered to reveal the product as atan solid in good yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.75 (m,6H) 1.85 (m, 2H) 3.29 (s, 3H) 3.73-3.97 (m, 2H) 3.93 (s, 3H) 4.94 (m,1H) 5.40-5.54 (m, 2H) 6.05 (m, 1H) 7.48-7.65 (m, 2H) 8.09 (d, J=8.34 Hz,1H) 8.23 (s, 1H) 9.51 (br. s., 1H). [M+H] calculated for C₂₃H₂₆FN₅O₄,456. found 456.

The compound4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid was separated into its enantiomers using SFC (ChiralPak OD-H insupercritical CO₂). The absolute chirality was determined byco-crystallization of one of the enantiomeric components with PLK1enzyme.

Compound 99:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-amino 1-N-methyl piperidine. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.53-1.86 (m, 8H) 1.93 (t, J=10.86 Hz, 4H) 2.16 (s, 3H) 2.78 (d,J=11.12 Hz, 2H) 3.28 (s, 3H) 3.65-3.83 (m, 4H) 3.93 (s, 3H) 4.88 (m, 1H)5.38 (d, J=11.87 Hz, 2H) 6.01 (m, 1H) 7.48 (d, J=8.0 Hz, 1H), 7.49 (br.s., 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.12 (d, J=7.83 Hz, 1H) 8.30 (d, J=8.0Hz, 1H). [M+H] calculated for C₂₉H₃₈FN₇O₃, 552. found 552.

Compound 100:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylazetidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-methylazetidin-3-amine bis-hydrochloride. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.48-2.10 (m, 8H) 2.32 (br. s., 3H) 3.08 (t, J=6.82Hz, 2H) 3.29 (br. s., 3H) 3.62 (t, J=6.95 Hz, 2H) 3.82 (m, 2H) 3.94 (br.s., 3H) 4.44 (m, 1H) 4.88 (m, 1H) 5.38 (d, J=12.13 Hz, 2H) 5.99 (m, 1H)7.50 (br. s., 2H) 7.84 (br. s., 1H) 8.13 (br. s., 1H)) 8.31 (d, J=8.0Hz, 1H) 8.65 (d, J=7.83 Hz, 1H). [M+H] calculated for C₂₇H₃₄FN₇O₃, 524.found 524.

Compound 101:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-amino 4-methylpiperazine. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.48-2.05 (m, 8H) 2.22 (br. s., 3H) 2.42 (m, 4H) 2.93 (t, J=4.55 Hz,4H) 3.28 (br. s., 3H) 3.72 (m, 2H) 3.93 (br. s., 3H) 4.87 (m, 1H) 5.39(d, 2H) 5.99 (m, 1H) 7.43 (br. s, 2H) 7.82 (s, 1H) 8.12 (br. s., 1H)8.32 (d, J=8.0 Hz, 1H) 9.36 (s, 1H). Melting point: 253-263° C. [M+H]calculated for C₂₈H₃₇FN₈O₃, 553. found 553.

Compound 102:4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N—((R)-piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing withwater (10 ml), t-butoxycarbonyl (Boc) protection group was removed using40% TFA in dichloromethane (6 ml) and purified the product usingpreparative HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-2.00 (m, 12H)2.39 (t, J=6.5 Hz, 2H) 2.81 (d, J=12.38 Hz, 1H) 2.96 (d, J=12.38 Hz, 1H)3.28 (s, 3H) 3.70-3.88 (m, 3H) 3.94 (s, 2H) 4.88 (m, 1H) 5.37 (d, 2H)6.00 (m, 1H) 7.47 (d, J=8.0 Hz, 1H), 7.48 (br. s., 1H) 7.82 (s, 1H) 7.98(d, J=8.0 Hz, 1H) 8.12 (s, 1H) 8.30 (d, J=8.0 Hz, 1H). Melting point:169-172° C. [M+H] calculated for C₂₈H₃₆FN₇O₃, 538. found 538.

Compound 103:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-amino 1-N-methyl piperidine. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00(m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H)3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd,J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s,2H) 8.30 (d, J=8.34 Hz, 1H). [M+H] calc'd for C₂₉H₃₈FN₇O₃, 552. found552.

Compound 104:(S)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from(S)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-amino 1-N-methyl piperidine. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00(m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H)3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd,J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s,2H) 8.30 (d, J=8.34 Hz, 1H) [M+H] calc'd for C₂₉H₃₈FN₇O₃, 552. found552.

Compound 105:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylpiperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 4-amino 1-N-ethyl piperidine. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.47-2.04 (m, 16H) 2.32 (q, J=7.07 Hz, 3H) 2.88 (d, J=11.62 Hz, 2H)3.28 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.87 (d, J=8.34 Hz, 1H)5.30-5.45 (m, 2H) 6.01 (ddd, J=17.43, 12.88, 10.86 Hz, 1H) 7.46 (d,J=1.77 Hz, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.08 Hz, 1H). [M+H]calc'd for C₃₀H₄₀FN₇O₃, 566. found 566.

Compound 106:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 2-(4-aminopiperidin-1-yl)ethanol. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.47-2.14 (m, 15H) 2.38 (t, J=6.32 Hz, 3H) 2.89 (d,J=11.62 Hz, 2H) 3.28 (s, 3H) 3.49 (q, J=6.23 Hz, 2H) 3.67-3.85 (m, 3H)3.94 (s, 3H) 4.37 (t, J=5.43 Hz, 1H) 4.89 (d, J=8.34 Hz, 1H) 5.28-5.48(m, 2H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1H) 7.40-7.54 (m, 2H) 7.82(s, 1H) 8.10 (d, J=7.58 Hz, 2H) 8.30 (d, J=8.34 Hz, 1H). [M+H] calc'dfor C₃₀H₄₀FN₇O₄, 582. found 582.

Compound 107:4-((R)-9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N—((R)-piperidin-3-yl)benzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing withwater (10 ml), t-butoxycarbonyl (Boc) protection group was removed using40% TFA in dichloromethane (6 ml) and purified the product usingpreparative HPLC and basified using sodium bicarbonate solution to givefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.33 (m, 2H) 1.30-1.80(m, 7H) 1.81-2.02 (m, 4H) 2.31-2.45 (m, 2H) 2.81 (d, J=12.63 Hz, 1H)2.97 (d, J=8.08 Hz, 1H) 3.29 (s, 3H) 3.71-3.90 (m, 3H) 3.94 (s, 3H) 4.89(d, J=8.59 Hz, 1H) 5.32-5.45 (m, 2H) 6.01 (ddd, J=17.56, 12.76, 10.86Hz, 1H) 7.41-7.53 (m, 2H) 7.82 (s, 1H) 8.00 (d, J=7.83 Hz, 1H) 8.12 (s,1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C₂₈H₃₆FN₇O₃, 538. found538.

Compound 108:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from(R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for amide bond synthesisusing HATU and 1-Boc-4-aminopiperidine. Further, after washing withwater (10 ml), t-butoxycarbonyl (Boc) protection group was removed using40% TFA in dichloromethane (6 ml). The resulting product was furtheracylated using N,N-dimethylacetyl chloride. The title product usingpreparative HPLC and neutralized with bicarbonate. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.41-2.05 (m, 12H) 2.19 (s, 6H) 2.92-3.21 (m, 4H) 3.28(s, 3H) 3.72-3.87 (m, 2H) 3.94 (s, 3H) 3.99-4.20 (m, 2H) 4.36 (d,J=15.41 Hz, 1H) 4.89 (d, J=8.34 Hz, 1H) 5.31-5.45 (m, 2H) 6.01 (ddd,J=17.49, 12.69, 10.74 Hz, 1H) 7.47 (d, J=1.77 Hz, 2H) 7.83 (s, 1H) 8.15(d, J=7.83 Hz, 2H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd forC₃₂H₄₃FN₈O₄, 623. found 623.

Compound 109:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide

The title compound was obtained from Compound 101 after chiralseparation using SFC (ChiralPak OD-H in supercritical CO₂). The absolutechirality was determined by co-crystallization of one of theenantiomeric components with PLK1 enzyme. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.48-2.05 (m, 8H) 2.22 (br. s., 3H) 2.42 (m, 4H) 2.93 (t, J=4.55 Hz,4H) 3.28 (br. s., 3H) 3.72 (m, 2H) 3.93 (br. s., 3H) 4.87 (m, 1H) 5.39(d, 2H) 5.99 (m, 1H) 7.43 (br. s., 2H) 7.82 (s, 1H) 8.12 (br. s., 1H)8.32 (d, J=8.0 Hz, 1H) 9.36 (s, 1H). [M+H] calculated for C₂₈H₃₇FN₈O₃,553. found 553.

Compound 110:(S)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide

The title compound was obtained from Compound 101 after chiralseparation using SFC (ChiralPak OD-H in supercritical CO₂). The absolutechirality was determined by co-crystallization of one of theenantiomeric components with PLK1 enzyme. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.48-2.05 (m, 8H) 2.22 (br. s., 3H) 2.42 (m, 4H) 2.93 (t, J=4.55 Hz,4H) 3.28 (br. s., 3H) 3.72 (m, 2H) 3.93 (br. s., 3H) 4.87 (m, 1H) 5.39(d, 2H) 5.99 (m, 1H) 7.43 (br. s., 2H) 7.82 (s, 1H) 8.12 (br. s., 1H)8.32 (d, J=8.0 Hz, 1H) 9.36 (s, 1H). [M+H] calculated for C₂₈H₃₇FN₈O₃,553. found 553.

Compound 111:(R)-2-(4-(4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamido)piperidin-1-yl)ethyl dihydrogen phosphate

The title compound was synthesized from(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methoxybenzamideas described in the procedure for the preparation of compound 41. Thefinal compound was purified by reverse phase HPLC and basified to givethe free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.82 (m, 9H)1.83-2.15 (m, 4H) 2.27-2.45 (m, 2H) 2.79-3.03 (m, 2H) 3.29 (s, 3H) 3.50(d, J=4.80 Hz, 2H) 3.66-3.86 (m, 3H) 3.94 (s, 3H) 4.21 (s, 1H) 4.39 (dd,J=11.12, 5.81 Hz, 1H) 5.29-5.47 (m, 2H) 6.01 (dd, J=17.43, 1.77 Hz, 1H)7.39-7.57 (m, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.31 (d, J=8.08 Hz, 1H) 9.88(s, 2H) [M+H] calc'd for C₃₀H₄₁FN₇O₇P 662. found 662.

Compound 112:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid

(R)- and(S)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:The racemic form of the title compounds was synthesized fromChloro-9-cyclopentyl-7-(1-hydroxyethyl)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-oneas described in general procedure. The enantiomers were separated usingSFC (CHIRAPAK AS 50 mm ID×500 mL, mobile phase:n-Hexane/2-Propanol=900/100 v/v.) Fraction 1 (F1) was(R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.The compound4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid was separated into its enantiomers using SFC (ChiralPak OD-H insupercritical CO₂). The absolute chirality was determined byco-crystallization of one of the enantiomeric components afterconversion to an amide with PLK1 enzyme. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.48-1.79 (m, 8H) 1.81-1.99 (m, 2H) 3.30 (s, 3H) 3.77-3.95 (m, 2H) 4.83(quin, J=8.27 Hz, 1H) 5.32-5.52 (m, 2H) 6.01 (ddd, J=17.43, 12.38, 11.12Hz, 1H) 8.21 (s, 1H) [M+H] calc'd for C₁₅H₁₈ClFN₄O 325. found 325.Fraction 2 (F2) was(S)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.79 (m, 8H) 1.81-1.99 (m, 2H) 3.30(s, 3H) 3.77-3.95 (m, 2H) 4.83 (quin, J=8.27 Hz, 1H) 5.32-5.52 (m, 2H)6.01 (ddd, J=17.43, 12.38, 11.12 Hz, 1H) 8.21 (s, 1H) [M+H] calc'd forC₁₅H₁₈ClFN₄O 325. found 325.

Methyl 4-amino-2-fluoro-5-methoxybenzoate: To an amount of4-amino-2-fluoro-5-methoxybenzoic acid (4 g, 21.62 mmole) that wasdissolved in DCM (40 ml) and MeOH (11 mL), was added TMS-diazomethane(16.2 mL, 32.43 mmole) slowly. The mixture was stirred at r.t for 30mins. After the removal of solvent, the resulting tan solid (4.0 g, 93%)carried onto the next reaction without any purification. [M+H] calc'dfor C₉H₁₀FNO₃, 200. found 200.

(R)-methyl4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoate:A mixture of(R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonicacid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture wasstirred at 95° C. for 24-48 h. The final compound was purified byreverse phase HPLC to give 400 mg product as white solid (40%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48-1.82 (m, 4H) 1.93-1.98 (m, 4H) 3.29 (s,3H) 3.51 (br. s., 2H) 3.61 (m, 3H), 3.86 (m, 3H) 3.94 (s, 3H) 4.88 (t,J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz,1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H).[M+H] calc'd for C₂₄H₂₇F₂N₅O₄, 488. found 488.

(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid: A mixture of (R)-methyl4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoate(400 mg, 0.821 mmol) was suspended in conc. HCl (1.0 mL) and it wasstirred at 95° C. for 3-4 hrs. At this time the reaction was cooled toroom temperature and filtered to reveal the product as a tan solid (295mg, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.82 (m, 4H) 1.98-2.02(m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz,1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57(m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'dfor C₂₃H₂₅F₂N₅O₄, 474. found 474.

Compound 113:(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from(R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 4-amino 1-methylpiperidine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.90 (m, 8H) 2.05 (dd, J=4.29,1.52 Hz, 4H) 2.16-2.28 (m, 2H) 2.34 (s, 3H) 2.83 (br. s., 2H) 3.39 (s,3H) 3.69-3.89 (m, 2H) 3.96 (s, 3H) 4.00-4.10 (m, 1H) 4.97 (quin, J=8.46Hz, 1H) 5.37 (d, J=11.12 Hz, 1H) 5.50 (dd, J=17.30, 1.89 Hz, 1H) 6.02(ddd, J=17.30, 14.53, 10.86 Hz, 1H) 6.67 (d, J=7.07 Hz, 1H) 7.56 (d,J=7.07 Hz, 1H) 7.76 (s, 1H) 7.96 (s, 1H) 8.37 (d, J=15.16 Hz, 1H), [M+H]calc'd for C₂₉H₃₇F₂N₇O₃ 570. found 570.

Compound 114:N-1-(2-amino-2-oxoethyl)piperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for the synthesis of thecompound 16 using HATU except that 2-(4-aminopiperidin-1-yl)acetamidewas used. The final compound was purified by reverse phase HPLC andbasified to give the free base. ¹H NMR (400 MHz, DMSO-d₆) □ ppm1.43-2.16 (m, 14H) 3.17 (br. s., 2H) 3.33 (s, 3H) 3.82-4.21 (m, 8H) 4.78(t, J=8.59 Hz, 1H) 7.51 (d, J=1.52 Hz, 2H) 7.73 (s, 1H) 7.98 (s, 1H)8.04-8.20 (m, 1H) 8.27 (s, 2H) 8.37 (d, J=7.07 Hz, 1H) 9.61 (br. s., 1H)[M+H] calc'd for C₂₈H₃₆F₂N₈O₄, 586. found 586.

Compound 115:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-3-methoxybenzamide

The title compound was synthesized from4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the General procedure for the synthesis of thecompound 16 using HATU except that2-(4-aminopiperidin-1-yl)-N,N-dimethylacetamide was used. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-2.17 (m, 14H) 2.94 (d,J=10.61 Hz, 6H) 3.01-3.20 (m, 2H) 3.33 (s, 3H) 4.06 (t, J=13.89 Hz, 5H)4.24 (d, J=4.55 Hz, 2H) 4.78 (t, J=7.45 Hz, 1H) 7.43-7.62 (m, 2H) 8.06(br. s., 1H) 8.27 (s, 2H) 8.36 (d, J=7.07 Hz, 1H) 9.52 (br. s., 1H)[M+H] calc'd for C₃₀H₄₀F₂N₈O₄, 614. found 614.

Compound 116:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 1-methylpiperidin-4-amine as described in the general procedurefor amide bond synthesis. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.60-1.73 (m, 11H), 1.88-2.21 (m, 8H) 2.78 (br. s., 2H) 3.73 (br.s., 1H) 3.91 (s, 3H) 4.08 (t, J=13.8 Hz, 2H) 4.81 (d, J=8.1 Hz, 1H) 7.18(d, J=6.6 Hz, 1H) 7.91 (br. s., 1H) 8.04 (s, 1H) 8.24 (d, J=13.4 Hz, 1H)8.30 (s, 1H). [M+H] calc'd for C₂₇H₃₄F₃N₇O₃, 562. found 562.

Compound 117:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-(2-hydroxyethyl)piperidin-4-yl)-5-methoxybenzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 2-(4-aminopiperidin-1-yl)ethanol as described in the Generalprocedure for amide bond synthesis. The final compound was purified byreverse phase HPLC and basified to give the free base. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.40-1.86 (m, 12H) 1.88-2.10 (m, 5H) 2.33-2.42 (m, 2H)2.84 (d, J=11.4 Hz, 2H) 3.48 (q, J=6.2 Hz, 2H) 3.73 (d, J=4.6 Hz, 1H)4.08 (t, J=14.0 Hz, 2H) 4.37 (t, J=5.4 Hz, 1H) 4.82 (t, J=8.2 Hz, 1H)7.18 (d, J=6.6 Hz, 1H) 7.90 (dd, J=7.7, 3.4 Hz, 1H) 8.04 (s, 1H)8.18-8.34 (m, 2H). [M+H] calc'd for C₂₈H₃₆F₃N₇O₄, 592. found 592.

Compound 118:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-2-fluoro-5-methoxybenzamide

Using the general procedure for amide bond synthesis,4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid was first reacted with tert-butyl 4-aminopiperidine-1-carboxylate.The product was diluted to ethyl acetate, washed by sodium bicarbonateaqueous solution and brine. Organic extract was dried and concentratedto a residue. It was then dissolved in a mixture of TFA and MeOH (1:1)and stirred for 1 h. After which, it was concentrated in vacuo,separated between ethyl acetate and sodium bicarbonate aqueous solution.Organic extract dried and concentrated to a residue, which was subjectedto amide bond synthesis with 2-(dimethylamino)acetic acid. The finalcompound was purified by reverse phase HPLC and basified to give thefree base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (m, 2H) 1.61 (m, 4H)1.73 (br. s., 4H) 1.99 (s, 3H) 2.19 (s, 6H) 2.73 (m, 1H) 3.14 (m, 3H)3.80-3.95 (m, 3H) 3.95-4.20 (m, 4H) 4.26 (m., 1H) 4.81 (d, J=8.1 Hz, 1H)7.19 (d, J=6.8 Hz, 1H) 7.92-8.10 (m, 2H) 8.18-8.35 (m, 2H). [M+H] calc'dfor C₃₀H₃₉F₃N₈O₄, 633. found 633.

Compound 119:(R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(piperidin-3-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and (R)-tert-butyl 3-aminopiperidine-1-carboxylate as described inthe General procedure for amide bond synthesis. The Boc group was thendeprotected using TFA. The final compound was purified by reverse phaseHPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.47 (m, 3H) 1.61 (m, 9H) 1.99 (s, 3H) 2.73 (m, 1H) 2.93 (m, 1H) 3.92(s, 4H) 4.01-4.20 (t, J=14 Hz, 2H) 4.82 (m, 1H) 7.24 (d, J=6.8 Hz, 1H)7.71-7.90 (m, 1H) 8.05 (s, 1H) 8.14-8.38 (m, 2H). [M+H] calc'd forC₂₆H₃₂F₃N₇O₃, 548. found 548.

Compound 120:9-Cyclopentyl-7,7-difluoro-2-(5-fluoro-2-methoxyphenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was a by-product from the reaction between thechloropyrimidine and 4-amino-2-fluoro-5-methoxybenzoic acid when heatedin isopropanol solution in presence of catalytic amount of concentratedHCl at 100° C. The final compound was purified by reverse phase HPLC. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.26 (d, J=6.3 Hz, 2H) 1.57 (m, 4H) 1.70(m, 2H) 1.92 (m, 2H) 3.80-3.93 (m, 3H) 4.05 (t, J=13.9 Hz, 2H) 4.62-4.85(m, 1H) 6.76 (td, J=8.5, 2.8 Hz, 1H) 7.01 (dd, J=8.8, 5.3 Hz, 1H) 7.91(s, 1H) 8.11 (dd, J=11.4, 2.8 Hz, 1H) 8.26 (s, 1H). [M+H] calc'd forC₂₀H₂₂F₃N₅O₂, 422. found 422.

Compound 121:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoicacid

5-Bromo-1,3-difluoro-2-nitrobenzene: To a mixture of acetic acid (30mL), 30% H₂O₂ (20 mL) and concentrated sulfuric acid (1 mL) was added1-bromo-2,6-difluoroaniline (5 g, 24 mmol) in acetic acid (10 mL)dropwise at 85° C. The reaction mixture was heated for 1 h. It was thencooled down, diluted to water and extracted with ethyl acetate. Theorganic layer was dried and concentrated to a red residue, which waspurified by flash column (EtOAc in Hexane 2-5%) to give the product asyellow solid (2.7 g, 47%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (m,2H).

5-Bromo-1-fluoro-3-methoxy-2-nitrobenzene: To a solution of5-bromo-1,3-difluoro-2-nitrobenzene (2.7 g, 11.3 mmol) in methanol (20mL) was added potassium hydroxide (680 mg, 12 mmol). The reactionmixture was refluxed at 90° C. for 1 h. It was then concentrated,diluted to ethyl acetate and washed by water and brine. The mixture wasthen purified by flash column to give the product as red oil (1.8 g,63%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 3H) 7.01 (s, 1H)7.04 (d, J=8 Hz, 1H).

3-Fluoro-5-methoxy-4-nitrobenzonitrile: A mixture of5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.5 g, 6 mmol), and CuCN (698mg, 7.8 mmol) in 10 mL of DMF was heated in a sealed tube at 160° C.overnight. It was then cooled down, diluted to ethyl acetate, washed bybrine and water. The organic extract was dried and concentrated to a redsolid (1 g, 85%) which was used for next step without furtherpurification. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3H) 7.14 (s,1H) 7.17 (d, J=8 Hz, 1H).

3-Fluoro-5-methoxy-4-nitrobenzoic acid. A suspension of3-fluoro-5-methoxy-4-nitrobenzonitrile (940 mg, 4.8 mmol) in a mixtureof concentrated H₂SO₄ and water (2 mL/2 mL) was heated at 100° C.overnight. The reaction mixture was then cooled down, solid filtered anddried to give the product as brown solid (770 mg, 75%).

4-Amino-3-fluoro-5-methoxybenzoic acid. A solution of3-fluoro-5-methoxy-4-nitrobenzoic acid (obtained above), HOAc (5 mL) andMeOH (5 mL) was hydrogenated using a hydrogen balloon overnight. Thesolution was then filtered through celite and concentrated to a redsolid (590 mg, 66%). [M+H] calc'd for C₈H₈FNO₃, 186. found 186.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoicacid: A mixture of the chloropyrimidine (158 mg, 0.5 mmol),4-amino-3-fluoro-5-methoxybenzoic acid (139 mg, 0.75 mmol), the catalystPd(OAc)₂ (12 mg, 0.05 mmol), the ligand XANTPHOS (58 mg, 0.1 mmol) andCs₂CO₃ (652 mg, 2 mmol) were dissolved in dioxane and N,N-dimethylacetamide (1 mL/1 mL). The reaction mixture was subjected to microwavereaction at 160° C. for 30 min. It was then poured to ice water,filtered through celite. The aqueous filtrate was acidified with HCl andextracted with ethyl acetate. The organic extract was dried andconcentrated to a residue which was purified by reverse phase HPLC (68mg, 30%). [M+H] calc'd for C₂₁H₂₂F₃N₅O₄, 466. found 466.

Compound 122:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-5-methoxybenzoicacid and 1-methylpiperidin-4-amine as described in the General procedurefor amide bond synthesis. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.33 (m, 4H) 1.58 (d, J=14.4 Hz, 6H) 1.75 (m, 2H) 1.93 (m, 2H)1.99 (s, 1H) 2.16 (s, 3H) 2.78 (d, J=10.6 Hz, 2H) 3.29 (s, 3H) 3.83 (s,2H) 3.89-4.01 (t, J=12 Hz, 2H) 4.32 (m, 1H) 7.24-7.48 (m, 2H) 8.10 (s,1H) 8.26 (d, J=7.6 Hz, 1H) 8.53 (s, 1H). [M+H] calc'd for C₂₇H₃₄F₃N₇O₃,562. found 562.

Compound 123:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoicacid

4-Bromo-3-fluoro-2-methoxyaniline: To 3-fluoro-2-methoxyaniline (2.8 g,20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) inacetic acid (10 mL) dropwise. The reaction mixture was stirred at rt.for 30 min. Solid was filtered and washed with acetic acid to give theHBr salt. It was then dissolved in water, basified by addition of KOH,extracted with ethyl acetate. The organic layer was dried andconcentrated to give a white solid (2.8 g, 80%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 3.93 (s, 3H) 6.42 (dd, J=8.6, 1.8 Hz, 1H) 7.01 (dd,J=8.6, 7.1 Hz, 1H). [M+H] calc'd for C₇H₇BrFNO, 222. found 222.

1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene: To4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFAand acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate(3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. andheated for 24 h. It was then diluted to water, extracted with ethylacetate. The product was obtained by flash column as a yellow solid (450mg, 40%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3H) 7.40 (dd,J=9.0, 6.2 Hz, 1H) 7.54 (dd, J=9.0, 1.9 Hz, 1H).

2-Fluoro-3-methoxy-4-nitrobenzonitrile: A mixture of1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene (250 mg, 1 mmol) and zinccyanide (70 mg, 0.6 mmol) were stirred in DMA (5 mL) and purged withnitrogen. The palladium catalyst, Pd₂(dba)₃ (92 mg, 0.1 mmol), and theligand, Davephos (79 mg, 0.2 mmol), were added and the reaction mixturewas stirred at 90° C. overnight. It was then cooled to rt., diluted toethyl acetate, washed with brine. Organic dried, concentrated andpurified by flash column (EtOAc/Hexane=1:20) to give 170 mg product(87%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.15 (s, 3H) 7.42 (dd,J=9.0, 6.2 Hz, 1H) 7.65 (dd, J=9.0, 1.9 Hz, 1H).

4-Amino-2-fluoro-3-methoxybenzoic acid: A solution of2-fluoro-3-methoxy-4-nitrobenzonitrile (170 mg) in H₂SO₄ and H₂O (0.5mL/0.5 mL) was heated at 100° C. for 18 h. After which, it was separatedbetween ethyl acetate and water. Organic extract was dried andconcentrated to give a residue, which was then dissolved in a mixture ofmethanol and acetic acid (2 mL/2 mL) and was hydrogenated using hydrogenballoon overnight. The solution was filtered through celite, and thefiltrate concentrated to give a read solid as the product. [M+H] calc'dfor C₈H₈FNO₃, 186. found 186.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoicacid: A mixture of the chloropyrimidine (145 mg, 0.46 mmol),4-amino-2-fluoro-3-methoxybenzoic acid (85 mg, 0.46 mmol), the catalystPd(OAc)₂ (11 mg, 0.05 mmol), the ligand XANTPHOS (58 mg, 0.1 mmol) andCs₂CO₃ (652 mg, 2 mmol) were dissolved in dioxane and N,N-dimethylacetamide (1.5 mL/1.5 mL). The reaction mixture was subjected tomicrowave reaction at 160° C. for 30 min. It was then poured to icewater, filtered through celite. The aqueous filtrate was acidified withHCl carefully and the solid was filtered, washed with water. The darksolid was then used for next step coupling without further purification.[M+H] calc'd for C₂₁H₂₂F₃N₅O₄, 466. found 466.

Compound 124:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoicacid and 1-methylpiperidin-4-amine as described in the General procedurefor amide bond synthesis. The final compound was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.37-1.66 (m, 7H) 1.75 (m, 4H) 1.82-2.04 (m, 4H) 2.15 (m, 3H)2.66-2.81 (m, 2H) 3.16 (s, 1H) 3.70 (m, 1H) 3.90 (s, 3H) 4.05 (t, J=13.8Hz, 2H) 4.77 (m, 1H) 7.24 (t, J=8.1 Hz, 1H) 7.96-8.13 (m, 2H) 8.26 (s,1H) 8.35 (s, 1H). [M+H] calc'd for C₂₇H₃₄F₃N₇O₃, 562. found 562.

Compound 125:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropylazetidin-3-yl)-3-methoxybenzamide

The title compound was synthesized by solubilizingN-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide(33 mg, 0.07 mmol) in acetic acid: methanol: dichloromethane (1 mL of1:2:2) and treatment with acetone (58 mg, 1.0 mmol), and borane-pyridine(100 μL, 0.8 mmol). The reaction was left to stir for 3 hours. Thereaction solvent was removed and the final compound was purified byreverse phase HPLC and basified to give the free base (5.7 mg, 16%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (d, J=6.06 Hz, 6H)1.48-1.78 (m, 8H) 1.93 (br. s., 2H) 2.24-2.36 (m, 1H) 2.94 (t, J=6.82Hz, 2H) 3.33 (s, 3H) 3.51 (t, J=6.82 Hz, 2H) 3.94 (s, 3H) 4.05 (t,J=14.02 Hz, 2H) 4.39 (q, J=6.99 Hz, 1H) 4.70-4.83 (m, 1H) 7.49 (d, 0H)7.51 (s, 1H) 7.98 (s, 1H) 8.26 (s, 1H) 8.29 (d, 1H) 8.61 (d, J=6.82 Hz,1H). [M+H] calculated for C₂₈H₃₇F₂N₇O₃, 574. found 574.

Compound 126:4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-3-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure for synthesizing compound 111 except that acetaldehyde wasused. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (t, J=7.20 Hz, 3H) 1.05-1.20(m, 2H) 1.23-1.40 (m, 2H) 1.48-1.63 (m, 3H) 1.66-1.83 (m, 4H) 3.25 (s,3H) 3.89 (s, 3H) 4.01 (t, J=13.26 Hz, 2H) 4.15 (br. s., 1H) 4.34-4.46(m, 1H) 4.54-4.68 (m, 1H) 7.44 (d, J=8.34 Hz, 1H) 7.47 (s, 1H) 7.89 (s,1H) 8.15 (s, 1H) 8.26 (d, J=8.34 Hz, 1H) 8.92 (br. s., 1H). [M+H]calculated for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 127:N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 3-amino-N—Boc-azetidine. The Boc group was then removedby treatment with 1:1 trifluoroacetic acid and dichloromethane for 1hour. At this time the solvent was removed and NaHCO₃ (sat.) and EtOAcwere added to the residue. The layers were separated, the organic layerwas then dried over MgSO₄, filtered, the solvent was removed and thefinal compound was purified by reverse phase HPLC and basified to givethe free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.79 (m, 6H) 1.93(br. s., 2H) 3.52-3.66 (m, 4H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H)4.56-4.84 (m, 2H) 7.45-7.58 (m, 2H) 7.98 (s, 1H) 8.26 (s, 1H) 8.28 (d,J=8.34 Hz, 1H) 8.75 (d, J=7.07 Hz, 1H). [M+H] calculated forC₂₄H₂₉F₂N₇O₃, 502. found 502.

Compound 128:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-3-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure usingN-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamideand acetaldehyde. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (t, J=7.20 Hz,3H) 1.49-1.76 (m, 6H) 1.93 (br. s., 2H) 2.45 (q, J=6.91 Hz, 2H) 2.98 (t,J=6.95 Hz, 1H) 3.33 (s, 3H) 3.56 (t, J=6.95 Hz, 2H) 3.94 (s, 3H) 4.05(t, J=14.02 Hz, 2H) 4.40-4.51 (m, 1H) 4.77 (t, 1H) 7.49 (d, 0H) 7.52 (s,1H) 7.98 (s, 1H) 8.26 (s, 1H) 8.29 (d, 1H) 8.66 (d, J=6.82 Hz, 1H).[M+H] calculated for C₂₆H₃₃F₂N₇O₃, 530. found 530.

Compound 129:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropylazetidin-3-yl)-3-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure usingN-(azetidin-3-yl)-4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamideand acetone. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (d, J=6.06 Hz, 6H)1.48-1.78 (m, 6H) 1.93 (br. s., 2H) 2.24-2.36 (m, 1H) 2.94 (t, J=6.82Hz, 2H) 3.33 (s, 3H) 3.51 (t, J=6.82 Hz, 2H) 3.94 (s, 3H) 4.05 (t,J=14.02 Hz, 2H) 4.39 (q, J=6.99 Hz, 1H) 4.70-4.83 (m, 1H) 7.49 (d, 0H)7.51 (s, 1H) 7.98 (s, 1H) 8.26 (s, 1H) 8.29 (d, 1H) 8.61 (d, J=6.82 Hz,1H). [M+H] calculated for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 130:N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 3-amino-N—Boc-azetidine. The Boc group was then removedby treatment with 1:1 trifluoroacetic acid and dichloromethane for 1hour. At this time the solvent was removed and NaHCO₃ (sat.) and EtOAcwere added to the residue. The layers were separated, the organic layerwas then dried over MgSO₄, filtered, the solvent was removed and thefinal compound was purified by reverse phase HPLC and basified to givethe free base. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.77 (m, 6H) 1.96(br. s., 2H) 3.56 (dd, J=7.45, 4.42 Hz, 4H) 3.91 (s, 3H) 4.08 (t,J=14.02 Hz, 2H) 4.62-4.73 (m, 1H) 4.76-4.90 (m, 1H) 7.20 (d, J=6.82 Hz,1H) 8.05 (s, 1H) 8.26 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.51 (d, J=3.54Hz, 1H). [M+H] calculated for C₂₄H₂₈F₃N₇O₃, 520. found 520.

Compound 131:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethylazetidin-3-yl)-2-fluoro-5-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure usingN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamideand acetaldehyde. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (t, J=7.20 Hz,3H) 1.61 (br. s., 6H) 1.96 (br. s., 2H) 2.40 (q, 2H) 2.88 (t, J=6.32 Hz,2H) 3.52 (t, J=5.81 Hz, 2H) 3.91 (s, 3H) 4.08 (t, J=13.77 Hz, 2H)4.33-4.48 (m, 1H) 4.71-4.89 (m, 1H) 7.20 (d, J=4.04 Hz, 1H) 8.05 (s, 1H)8.26 (d, J=13.39 Hz, 1H) 8.31 (d, J=3.28 Hz, 1H) 8.43 (d, J=7.07 Hz,1H). [M+H] calculated for C₂₆H₃₂F₃N₇O₃, 548. found 548.

Compound 132:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-isopropylazetidin-3-yl)-5-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure usingN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamideand acetone. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85 (d, J=6.06 Hz, 6H)1.44-1.80 (m, 6H) 1.95 (br. s., 2H) 2.27 (m, 6.09 Hz, 1H) 2.89 (t,J=7.33 Hz, 2H) 3.50 (t, J=7.33 Hz, 2H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz,2H) 4.29-4.42 (m, 1H) 4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s,1H) 8.25 (d, J=13.39 Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H).[M+H] calculated for C₂₇H₃₄F₃N₇O₃, 562. found 562.

Compound 133:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentylazetidin-3-yl)-2-fluoro-5-methoxybenzamide

The title compound was synthesized by following the Reductive AminationProcedure usingN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamideand cyclopentanone. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23-1.35 (m, 2H)1.38-1.78 (m, 11H) 1.96 (br. s., 2H) 2.67 (br. s., 1H) 2.87 (t, J=7.33Hz, 2H) 3.49 (t, J=7.33 Hz, 2H) 3.91 (s, 3H) 4.08 (t, J=13.77 Hz, 2H)4.33-4.44 (m, 1H) 4.78-4.88 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 8.05 (s, 1H)8.25 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.41 (dd, J=6.82, 3.03 Hz, 1H).[M+H] calculated for C₂₉H₃₆F₃N₇O₃, 588. found 588.

Compound 134:9-cyclopentyl-2-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-2-methoxyphenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized from4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 1-(cyclopropylmethyl)piperazine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.07 (br. s., 2H) 0.47 (br. s., 2H) 1.55 (br. s., 5H)1.68 (br. s., 2H) 1.90 (br. s., 2H) 2.21 (br. s., 1H) 2.40-2.48 (m, 3H)3.31 (s, 4H) 3.32 (br. s., 3H) 3.88 (s, 3H) 4.03 (t, J=13.89 Hz, 2H)4.64-4.76 (m, 1H) 6.96 (d, J=8.84 Hz, 1H) 7.04 (s, 1H) 8.00 (s, 1H) 8.15(d, J=7.83 Hz, 1H) 8.23 (s, 1H). [M+H] calculated for C₂₉H₃₇F₂N₇O₃, 570.found 570.

Compound 135:9-cyclopentyl-2-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-5-fluoro-2-methoxyphenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 1-(cyclopropylmethyl)piperazine. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.07 (d, J=4.55 Hz, 2H) 0.45 (d, J=8.08 Hz, 2H) 0.75-0.87(m, 1H) 1.47-1.77 (m, 6H) 1.92 (br. s., 2H) 2.20 (d, J=6.57 Hz, 2H)2.32-2.43 (m, 2H) 3.22-3.31 (m, 2H) 3.64 (br. s., 2H) 3.88 (s, 3H) 4.06(t, J=13.77 Hz, 3H) 4.70-4.84 (m, 1H) 6.97 (d, J=6.06 Hz, 1H) 8.04 (s,1H) 8.16 (d, J=11.87 Hz, 1H) 8.28 (s, 1H). [M+H] calculated forC₂₉H₃₆F₃N₇O₃, 588. found 588.

Compound 136:9-cyclopentyl-2-(2,2-difluorobenzo[d][1,3]dioxol-4-ylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

The title compound was synthesized from2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-oneand 2,2-difluorobenzo[d][1,3]dioxol-4-amine using the proceduredescribed in the general Buchwald Reaction Scheme. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.20-1.84 (m, 9H) 3.97 (t, J=14.40 Hz, 2H) 4.50-4.70 (m,1H) 7.14 (d, J=2.27 Hz, 1H) 7.31 (dd, J=7.45, 2.15 Hz, 1H) 8.21 (s, 1H)9.39 (s, 1H). [M+H] calculated for C₂₀H₁₉F₄N₅O₃, 454. found 454.

Compound 137:(4-(9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxyphenyl)methanol

The title compound was synthesized by solubilizing4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (0.36 mmol) in THF (20 mL), and adding borane-dimethylsulfide(2.0M, 1.8 mL, 3.6 mmol) slowly. The solution was stirred for 18 h andthen heated to 50° C. for 2 hours. The reaction mixture was then washedwith water (×2), brine, and the solvent evaporated. The final compoundwas purified by reverse phase HPLC and basified to give the free base(8.1 mg, 5% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.96 (m, 8H)2.82 (s, 3H) 3.48 (t, J=13.39 Hz, 2H) 3.78 (t, J=12.00 Hz, 2H) 3.86 (s,3H) 4.43 (d, 2H) 4.84 (t, J=7.83 Hz, 1H) 5.07 (t, J=5.81 Hz, 1H) 6.82(d, J=8.34 Hz, 1H) 6.95 (s, 1H) 7.31 (s, 1H) 7.66 (s, 1H) 8.21 (d,J=8.08 Hz, 1H). [M+H] calculated for C₂₁H₂₇F₂N₅O₂, 420. found 420.

Compound 138:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized by first following the general RingAmide Reduction procedure using isopropyl4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoateto yield isopropyl4-(9-cyclopentyl-7,7-difluoro-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoate.This ester was then saponified by treating with 4N HCl and MeOH (10:1)and heating 100° C. overnight. The solvent was evaporated and the titleamide formed as described in the general procedure for amide bondsynthesis using HATU and 4-amino-N-methylpiperidine. 1H NMR (400 MHz,DMSO-d₆) δ ppm 1.51-1.97 (m, 8H) 2.16 (s, 3H) 2.78 (d, J=10.61 Hz, 2H)2.83 (s, 3H) 3.31 (br. s., 10H) 3.50 (t, J=13.52 Hz, 2H) 3.81 (t,J=12.13 Hz, 2H) 3.93 (s, 3H) 4.72-4.93 (m, 1H) 7.46 (s, 1H) 7.52 (s, 1H)7.70 (s, 1H) 8.06 (d, J=7.83 Hz, 1H) 8.39 (d, J=8.34 Hz, 1H). [M+H]calculated for C₂₇H₃₇F₂N₇O₂, 530. found 530.

Compound 139:3-(cyclopentyl(2-(2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-5-(methylamino)pyrimidin-4-yl)amino)-2,2-difluoropropanoicacid

To a mixture of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide(543 mg, 1 mmol) in 10 ml of DMF, was added 1N NaOH (5 ml) dropwise. Thereaction mixture was stirred at rt. for 1 h and then subjected toreverse phase HPLC purification using basic column. The final compoundwas obtained by lyophilization first and then dried in the vacuum ovenat 60° C. for 3 d (380 mg, 68%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.47-1.99 (m, 12H) 2.54 (d, J=2.8 Hz, 2H) 2.64-2.79 (m, 5H) 3.00 (d,J=4.6 Hz, 2H) 3.85-4.10 (m, 6H) 4.20 (d, J=7.3 Hz, 1H) 7.42 (s, 2H) 7.48(d, J=8.3 Hz, 1H) 7.61-7.80 (m, 1H) 8.23 (br. s., 1H) 8.42 (d, J=8.3 Hz,1H). [M+H] calc'd for C₂₇H₃₇F₂N₇O₄, 562. found 562.

Compound 140:3-(cyclopentyl(2-(5-fluoro-2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)phenylamino)-5-(methylamino)pyrimidin-4-yl)amino)-2,2-difluoropropanoicacid

To a mixture of compound 116 (300 mg, 0.53 mmol) in 2 ml of DMF, wasadded 1N NaOH (1 ml) dropwise. The reaction mixture was stirred at rt.for 1 h and then subjected to reverse phase HPLC purification usingbasic column (Gemini 5μ C18 column, mobile phase A: H₂O; B: 20% H₂O inCH₃CN which contains 10 μM NH₄HCO₃). The final compound was directlylyophilized and then dried in the vacuum oven at 60° C. for 3 days togive 234 mg white solid (76%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.98(m, 12H) 2.60-2.81 (m, 6H) 3.03 (m, 2H) 3.79-4.08 (s&m, 6H) 4.16 (m, 1H)7.14 (d, J=6.8 Hz, 1H) 7.52 (s, 1H) 7.71 (s, 1H) 8.03 (br. s., 1H)8.34-8.38 (d, J=16 Hz, 1H) 9.81 (br. s., 1H). [M+H] calc'd forC₂₇H₃₆F₃N₇O₄, 580. found 580.

Compound 141:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Methyl 3-amino-2,2-difluoropropanoate-HCl salt: In a round bottom flask,3-amino-2,2-difluoropropanoic acid (500 mg, 4 mmol) was solubilized inMeOH (10 mL). At 0° C., SOCl₂ (1 mL) was added dropwise. The reactionmixture was then stirred at room temperature overnight. Evaporation ofthe reaction mixture gave a white solid to be the product as HCl salt(570 mg, 81%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.63 (t, J=16 Hz, 2H)3.87 (s, 3H) 9.07 (br. s., 2H).

Methyl 3-(cyclopentylamino)-2,2-difluoropropanoate: To a round bottomflask was added methyl 3-amino-2,2-difluoropropanoate (570 mg, 3.24mmol), THF (20 mL), cyclopentanone (0.433 mL, 4.87 mmol), and HOAc (1mL). To this mixture was added sodium triacetoxyborohydride (1.06 g, 5mmol) portionwise. The reaction was left to stir overnight. It was thenadded slowly to a stirring solution of ice, NaHCO₃ (sat.), and EtOAc.The aqueous layer was further extracted with EtOAc, the organic extractscombined, dried over MgSO₄, filtered and concentrated to yield thedesired product as clear syrup (400 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.30 (td, J=13, 6 Hz, 2H) 1.43 (d, J=8 Hz, 1H) 1.47-1.70 (m, 4H)1.77 (dt, J=12, 6 Hz, 2H) 3.12 (t, J=6 Hz, 1H) 3.19 (t, J=14 Hz, 2H)3.88 (s, 3H).

Methyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate:Compound methyl 3-(cyclopentylamino)-2,2-difluoropropanoate (400 mg, 2mmol) was solubilized in acetone (20 mL, dry). The solution was cooledin an ice water bath under a nitrogen atmosphere and K₂CO₃ (552 mg, 4mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (407mg, 2.1 mmol) in acetone (5 mL, dry) was added dropwise. The reactionmixture was warmed up to room temperature and stirred for 4 hr. Afterthat, it was diluted with EtOAc and washed by brine and water. Theorganic extracts were dried over MgSO₄, filtered and concentrated toyield the desired product which was used directly for next step withoutfurther purification. [M+H] calc'd for C₁₃H₁₅ClF₂N₄O₄, 365. found 365.

2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:Above obtained compound, methyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate,was dissolved in AcOH (10 mL). Iron powder (224 mg, 4 mmol) was addedfollowed by the slow addition of HCl (1.5 mL, conc.). The reactionmixture was left to stir at 60° C. for 1 hr. The reaction was thencooled, the stir bar and unreacted iron removed by filtration throughpaper, and the solvent volume reduced by about 75% on a rotovap. Themixture was then diluted with ice water and EtOAc. Aqueous layerbasified by careful addition of sat. NaHCO₃. The organic extractscombined, dried over MgSO₄, filtered and concentrated to yield a brownsyrup (550 mg) which was used directly for next step without furtherpurification. [M+H] calc'd for C₁₂H₁₃ClF₂N₄O, 303. found 303.

2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one:2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(550 mg, 1.82 mmol) was dissolved in DMA (10 mL) and cooled in an icebath. Sodium hydride (80 mg of 60% in mineral oil, 2 mmol) was addedslowly and left to stir for 10 minutes. Methyl iodide (0.125 mL, 2 mmol)was then added and the reaction mixture was warmed up to roomtemperature. After 30 minutes the reaction was deemed complete by LCMS,poured into ice water, the solution extracted with EtOAc. The organiclayer washed with brine and water, dried over MgSO₄, and concentrated togive a brown residue which was used directly for next step. [M+H] calc'dfor C₁₃H₁₅ClF₂N₄O, 317. found 317.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid:2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(obtained above), 4-amino-3-methoxy benzoic acid (334 mg, 2 mmol),i-PrOH (10 mL) and conc. HCl (10 drops) were heated to 100° C.overnight. The reaction mixture was then cooled to room temperature,concentrated and redissolved in MeOH, treated with NaOH and refluxed for1 hr. After which, it was concentrated, acidified with HCl and filteredto get the product as a tan solid (300 mg). [M+H] calc'd forC₂₁H₂₃F₂N₅O₄, 448. found 448.

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (obtained above, 300 mg) as described in the general procedure foramide bond synthesis using HATU and 1-methylpiperidin-4-amine. The finalcompound was purified by reverse phase HPLC and basified to give thefree base (40 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-2.01 (m, 16H)2.17 (s, 3H) 2.78 (d, J=11 Hz, 2H) 3.28 (s, 1H) 3.33 (s, 3H) 3.73 (m.,1H) 3.94 (s, 3H) 4.04 (t, J=14 Hz, 2H) 4.76 (m, 1H) 7.47 (s, 1H) 7.50(s, 1H) 7.95 (s, 1H) 8.09 (d, J=8 Hz, 1H) 8.26 (d, J=8 Hz, 1H) 8.26 (s,1H). [M+H] calc'd for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 142:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

2-Fluoro-5-methoxy-4-nitrobenzoic acid: To a solution ofmethyl-2,5-difluoro-4-nitrobenzoate (1 g, 4.6 mmol) in methanol (10 mL)was added sodium methoxide (95%, 393 mg, 6.9 mmol). The reaction mixturewas stirred at room temperature overnight. It was then concentrated,acidified with HCl. Solid was filtered and dried to give the product aslight yellow powder (728 mg, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95(s, 3H) 7.66 (d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H).

4-Amino-2-fluoro-5-methoxybenzoic acid: A solution of ethyl2-fluoro-5-methoxy-4-nitrobenzoic acid (217 mg, 1 mmol), HOAc (cat.) andMeOH (10 mL) was hydrogenated using H-cube hydrogenator. The solutionwas then concentrated and dried to give the product which can be usedfor next step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δppm 3.76 (s, 3H) 5.88 (br s, 2H) 6.36 (d, J=16 Hz, 1H) 7.13 (d, J=8 Hz,1H) 12.32 (br s, 1H).

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid:2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(158 mg, 0.5 mmol), 4-amino-2-fluoro-5-methoxy benzoic acid (obtainedabove), i-PrOH (5 mL) and conc. HCl (10 drops) were heated to 100° C.overnight. The reaction mixture was then cooled to room temperature. Thereaction mixture contains desired product plus lots of de-carboxylationbyproduct, which were separated by RP-HPLC to give the product as awhite solid (12 mg). [M+H] calc'd for C₂₁H₂₂F₃N₅O₄, 466. found 466.

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid (obtained above, 12 mg) as described in the general procedure foramide bond synthesis using HATU and 1-methylpiperidin-4-amine. The finalcompound was purified by reverse phase HPLC and basified to give thefree base (8 mg, 55%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.73 (m,11H), 1.88-2.21 (m, 8H) 2.78 (br. s., 2H) 3.73 (br. s., 1H) 3.91 (s, 3H)4.08 (t, J=14 Hz, 2H) 4.81 (d, J=8 Hz, 1H) 7.18 (d, J=7 Hz, 1H) 7.91(br. s., 1H) 8.04 (s, 1H) 8.24 (d, J=13 Hz, 1H) 8.30 (s, 1H). [M+H]calc'd for C₂₇H₃₄F₃N₇O₃, 562. found 562.

Compound 143:9-Cyclopentyl-2-(2,5-difluorophenylamino)-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(50 mg, 0.16 mmol), 2,5-difluoroaniline (31 mg, 0.24 mmol), i-PrOH (2mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give thetitle compound. The final compound was purified by reverse phase HPLCand basified to give the free base (20 mg, 31%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.23-1.85 (m, 11H) 4.02 (t, J=14 Hz, 2H) 4.68 (d, J=8 Hz,1H) 6.88 (t, J=8 Hz, 1H) 7.26 (td, J=10, 6 Hz, 1H) 7.74-7.96 (m, 1H)8.24 (s, 1H) 9.04 (br. s., 1H). [M+H] calc'd for C₁₉H₁₉F₄N₅O, 410. found410.

Compound 144:9-Cyclopentyl-7,7-difluoro-2-(3-fluorophenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(100 mg, 0.32 mmol), 3-fluoroaniline (54 mg, 0.48 mmol), i-PrOH (2 mL)and conc. HCl (5 drops) were heated to 100° C. overnight to give thetitle compound. The final compound was purified by reverse phase HPLCand basified to give the free base (50 mg, 40%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.58-1.96 (m, 8H) 4.04 (t, J=14 Hz, 2H) 4.78 (m, 1H)6.59-6.87 (m, 1H) 7.16-7.33 (m, 1H) 7.38 (d, J=8 Hz, 1H) 7.79 (d, J=12Hz, 1H) 8.26 (s, 1H) 9.66 (br. s., 1H). [M+H] calc'd for C₁₉H₂₀F₃N₅O,392. found 392.

Compound 145:9-Cyclopentyl-7,7-difluoro-2-(5-fluoro-2-methylphenylamino)-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(100 mg, 0.32 mmol), 5-fluoro-2-methylaniline (60 mg, 0.48 mmol), i-PrOH(2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to givethe title compound. The final compound was purified by reverse phaseHPLC and basified to give the free base (50 mg, 39%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.40-1.96 (m, 9H) 2.22 (s, 3H) 3.99 (t, J=14 Hz, 2H) 4.62(t, J=8 Hz, 1H) 6.81 (td, J=8, 3 Hz, 1H) 7.19 (t, J=8 Hz, 1H) 7.58 (dd,J=12, 3 Hz, 1H) 8.20 (s, 1H) 8.57 (s, 1H). [M+H] calc'd for C₂₀H₂₂F₃N₅O,406. found 406.

Compound 146:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methyl-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methylbenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC and basified to give the free base. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.77 (m, 11H) 1.98 (m, 4H) 2.16 (s,3H) 2.31 (s, 3H) 2.75 (d, J=11 Hz, 2H) 3.17 (br. s., 2H) 3.67 (d, J=7Hz, 1H) 4.03 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.22 (d, J=8 Hz, 1H) 7.46 (d,J=8 Hz, 1H) 7.68 (br. s., 1H) 7.99 (d, J=8 Hz, 1H) 8.25 (s, 1H) 9.51(br. s., 1H). [M+H] calc'd for C₂₇H₃₅F₂N₇O₂, 528. found 528.

Compound 147:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methoxy-N-(1-methylpiperidin-4-yl)benzamide

The title compound was synthesized from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-methoxybenzoicacid as described in the general procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.48-2.22 (m, 14H) 2.66-2.88 (m, 2H) 3.05 (m, 2H) 3.33 (s, 3H) 3.46 (d,J=11 Hz, 2H) 3.86 (s, 3H) 4.05 (t, J=14 Hz, 3H) 4.81 (m, 1H) 7.49 (m,2H) 7.64 (m, 1H) 7.93 (d, J=7 Hz, 1H) 8.28 (s, 1H) 9.69 (s, 1H). [M+H]calc'd for C₂₇H₃₅F₂N₇O₃, 544. found 544.

Compound 148:5-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methylpiperidin-4-yl)picolinamide

The title compound was synthesized from5-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)picolinicacid as described in the general procedure for amide bond synthesisusing HATU and 1-methylpiperidin-4-amine. The final compound waspurified by reverse phase HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.44-2.04 (m, 13H) 2.77 (d, J=5 Hz, 2H) 3.01-3.22 (m, 2H) 3.34 (s, 3H)3.47 (d, J=11 Hz, 2H) 4.08 (m, 3H) 4.80 (m, 1H) 7.85-8.02 (m, 1H) 8.30(s, 1H) 8.44 (dd, J=9, 2 Hz, 1H) 8.69 (d, J=8 Hz, 1H) 8.80-8.92 (m, 1H)9.85-10.01 (m, 1H). [M+H] calc'd for C₂₅H₃₂F₂N₈O₂, 516. found 516.

Compound 149:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

In a dry round bottom flask,4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (89.4 mg, 0.2 mmol), 4-((4-methylpiperazin-1-yl)methyl)anilinehydrochloride (66.7 mg, 0.24 mmol) were dissolved in dryN,N-dimethylformamide (3.0 mL). Then added diisopropylethylamine (107μL, 0.6 mmol) and finally HATU (114 mg, 0.3 mmol) to the reaction,continued at room temperature for 2 hours. After completion, purifiedthe product using reverse phase HPLC using water-acetonitrile solventsystem. Pure fractions were mixed and evaporated to a minimal amountthen basified with sat.NaHCO₃ solution and extracted into EtOAc ((2×100mL), combined organic layer was washed with sat. brine solution, driedover Na₂SO₄ and evaporated to get the pure product 72 mg (57% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.80 (m, 6H) 1.97 (br. s., 2H) 2.15(s, 3H) 2.34 (br. s., 8H) 3.42 (s, 2H) 3.93 (s, 3H) 4.07 (t, J=12 Hz,2H) 4.80 (t, J=8.21 Hz, 1H) 7.26 (d, J=8.59 Hz, 2H) 7.51-7.67 (m, 2H)7.70 (m, J=8.59 Hz, 2H) 8.05 (s, 1H) 8.29 (s, 1H) 8.37 (d, J=8.34 Hz,1H) 10.09 (s, 1H). [M+H] calc'd for C₃₃H₄₀F₂N₈O₃, 635. found 635.

Compound 150A:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-3-methoxybenzamide

The title compound was prepared in a manner analogous to the compound149 from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 52.4 mg(41%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (br. s., 6H) 1.99 (s, 2H)2.22 (s, 3H) 2.40-2.51 (m, 4H) 2.98 (br. s., 4H) 3.97 (s, 3H) 4.22 (t,2H) 4.79 (m, 1H) 7.03 (t, J=9.35 Hz, 1H) 7.45 (dd, J=8.72, 1.64 Hz, 1H)7.54-7.78 (m, 3H) 8.04 (s, 1H) 8.28 (s, 1H) 8.36 (d, J=8.34 Hz, 1H)10.11 (s, 1H). [M+H] calc'd for C₃₂H₃₇F₂N₈O₃, 639. found 639.

Compound 150B4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid and 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)aniline withyield 46 mg (34%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43-1.72 (m, 6H)1.99 (br. s., 2H) 2.23 (s, 3H) 2.47 (br.s., 4H) 2.85 (t, J=4.29 Hz, 4H)3.99 (s, 3H) 4.07 (t, J=12 Hz, 2H) 4.80 (t, J=7.96 Hz, 1H) 7.46-7.73 (m,3H) 7.97-8.10 (m, 2H) 8.14 (d, J=2.53 Hz, 1H) 8.29 (s, 1H) 8.38 (d,J=8.34 Hz, 1H) 10.31 (s, 1H). [M+H] calc'd for C₃₃H₃₇F₅N₈O₃, 689. found689.

Compound 151:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)benzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid and 3-(4-methylpiperazin-1-yl)aniline with yield 35 mg (28%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.43-1.72 (m, 6H) 1.98 (br. s., 2H) 2.22(s, 2H) 2.35-2.50 (m, 4H) 2.97-3.23 (m, 4H) 3.98 (s, 3H) 4.06 (t, J=12Hz, 2H) 4.79 (m, 1H) 6.55-6.79 (m, 1H) 7.12-7.26 (m, 2H) 7.40 (s, 1H)7.52-7.72 (m, 2H) 8.03 (s, 1H) 8.28 (s, 1H) 8.35 (d, J=8.34 Hz, 1H) 9.94(s, 1H). [M+H] calc'd for C₃₂H₃₈F₂N₈O₃, 621. found 621.

Compound 152:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride withyield 48 mg (37%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62 (br. s., 4H)1.73 (br. s., 2H) 1.98 (m, 2H) 2.14 (s, 3H) 2.17-2.45 (m, 8H) 3.40 (s,2H) 3.94 (s, 3H) 4.09 (t, J=12 Hz, 2H) 4.84 (t, J=8.08 Hz, 1H) 7.16-7.37(m, 3H) 7.66 (d, J=8.34 Hz, 2H) 8.10 (s, 1H) 8.19-8.39 (m, 2H) 10.13 (s,1H). [M+H] calc'd for C₃₃H₃₉F₃N₈O₃, 653. found 653.

Compound 153:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 3-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride withyield 43 mg (33%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62 (br. s., 6H)1.99 (br. s., 2H) 2.14 (s, 3H) 2.33 (br. s., 8H) 3.43 (s, 2H) 3.94 (s,3H) 4.09 (t, J=13.89 Hz, 2H) 4.84 (br. s., 1H) 7.01 (d, J=7.58 Hz, 1H)7.20-7.35 (m, 2H) 7.61 (br. s., 1H) 7.67 (br. s., 1H) 8.10 (s, 1H)8.23-8.40 (m, 2H) 10.14 (s, 1H). [M+H] calc'd for C₃₃H₃₉F₃N₈O₃, 653.found 653.

Compound 154:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-5-methoxybenzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 70 mg(53%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42-1.73 (m, 6H) 1.86-2.06 (m,2H) 2.22 (s, 3H) 2.35-2.49 (m, 4H) 2.97 (br. s., 4H) 3.94 (s, 3H) 4.09(t, J=13.89 Hz, 2H) 4.82 (t, J=7.83 Hz, 1H) 7.01 (t, J=9.35 Hz, 1H) 7.26(d, J=6.82 Hz, 1H) 7.32-7.45 (m, 1H) 7.63 (dd, J=15.03, 1.89 Hz, 1H)8.10 (s, 1H) 8.19-8.46 (m, 2H) 10.16 (s, 1H). [M+H] calc'd forC₃₂H₃₆F₄N₈O₃, 657. found 657.

Compound 155:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)benzamide

The title compound was prepared in a manner analogous to compound 149from4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid and 4-(4-methylpiperazin-1-yl)aniline with yield 82 mg (53%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.61 (br. s., 4H) 1.73 (br. s., 2H) 1.99(br. s., 2H) 2.22 (s, 3H) 2.45 (br. s., 4H) 3.09 (br. s., 4H) 3.94 (s,3H) 4.08 (t, J=13.89 Hz, 2H) 4.84 (br. s., 1H) 6.91 (d, J=8.84 Hz, 2H)7.26 (d, J=6.32 Hz, 1H) 7.56 (d, J=8.59 Hz, 2H) 8.08 (s, 1H) 8.18-8.41(m, 2H) 9.91 (br. s., 1H). [M+H] calc'd for C₃₂H₃₇F₃N₈O₃, 639. found639.

Compound 156:N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide

To a solution of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoicacid (1 g, 2.2 mmol) in DMF (4 mL) was added tert-butyl3-aminoazetidine-1-carboxylate (413 mg, 2.4 mmol), HATU (1.43 g, 3.75mmol), and DIEA (973 μL, 5.5 mmol). The reaction mixture was stirred for1 h. It was then poured into 100 mL of rapidly stirring water. A darkbrown solid forms and was filtered, washed with water and dried to give884 mg of the Boc protected intermediate. This solid was treated withTFA in DCM (10 mL 1:1) for 30 minutes. The solvent was then removed, andthe residue partitioned between ethyl acetate and sodium bicarbonate(sat. aq.). The layers were separated and the aqueous layer was furtherextracted with a portion of DCM with 3% MeOH. The organic layers werecombined, dried over MgSO₄, filtered and concentrated to yield a browntar (568 mg, 50% yield) which was used crude in subsequent reactions. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.77 (m, 6H) 1.96 (br. s., 2H) 3.56(dd, J=7.45, 4.42 Hz, 3H) 3.91 (s, 2H) 4.08 (t, J=14.02 Hz, 2H)4.62-4.73 (m, 1H) 4.76-4.90 (m, 1H) 7.20 (d, J=6.82 Hz, 1H) 8.05 (s, 1H)8.26 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.51 (d, J=3.54 Hz, 1H). [M+H]calc'd for C₂₄H₂₈F₃N₇O₃, 520. found 520.

Compound 157:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-N-(1-isopropylazetidin-3-yl)-5-methoxybenzamide

To a solution ofN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide(100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was added acetone(100 μL, 1.36 mmol), borane-pyridine complex (100 μL, 0.8 mmol), andleft to stir for 3 h. The solvent was then removed and the productpurified by reverse phase HPLC, free based, and lyophilized to yield awhite solid (3.3 mg, 3%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85 (d,J=6.06 Hz, 4H) 1.05 (d, J=6.57 Hz, 2H) 1.44-1.80 (m, 6H) 1.95 (br. s.,2H) 2.27 (dt, J=12.32, 6.09 Hz, 1H) 2.89 (t, J=7.33 Hz, 2H) 3.50 (t,J=7.33 Hz, 1H) 3.92 (s, 3H) 4.08 (t, J=13.89 Hz, 2H) 4.29-4.42 (m, 1H)4.72-4.89 (m, 1H) 7.19 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.25 (d, J=13.39Hz, 1H) 8.29-8.32 (m, 1H) 8.40 (d, J=7.07 Hz, 1H). [M+H] calc'd forC₂₇H₃₄F₃N₇O₃, 562. found 562.

Compound 158:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentylazetidin-3-yl)-2-fluoro-5-methoxybenzamide

To a solution ofN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide(100 mg, 0.19 mmol) in AcOH:DCM:MeOH (2.5 mL, 1:2:2) was addedcyclopentanone (100 μL, 1.09 mmol), borane-pyridine complex (100 μL, 0.8mmol), and left to stir for 3 h. The solvent was then removed and theproduct purified by reverse phase HPLC, free based, and lyophilized toyield a white solid (5.0 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.23-1.35 (m, 2H) 1.38-1.78 (m, 11H) 1.96 (br. s., 2H) 2.67 (br. s., 1H)2.87 (t, J=7.33 Hz, 2H) 3.49 (t, J=7.33 Hz, 2H) 3.91 (s, 3H) 4.08 (t,J=13.77 Hz, 2H) 4.33-4.44 (m, 1H) 4.78-4.88 (m, 1H) 7.19 (d, J=6.57 Hz,1H) 8.05 (s, 1H) 8.25 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.41 (dd, J=6.82,3.03 Hz, 1H). [M+H] calc'd for C₂₉H₃₆F₃N₇O₃, 588. found 588.

Compound 159:N-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide

To a solution of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl3-aminoazetidine-1-carboxylate (41.3 mg, 0.24 mmol), HATU (125 mg, 0.33mmol), and DIEA (80 μL, 0.44 mmol). The reaction mixture was stirred for1 h. It was then poured into 100 mL of rapidly stirring water. A peachsolid forms and was filtered, washed with water and dried. This solidwas treated with TFA in DCM (3 mL 1:1) for 30 minutes. The solvent wasthen removed, and the product purified by reverse phase HPLC, free basedand lyophilized to yield a white solid (37.4 mg, 34% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.49-1.79 (m, 6H) 1.93 (br. s., 2H) 3.52-3.66 (m,4H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H) 4.56-4.84 (m, 2H) 7.45-7.58(m, 2H) 7.98 (s, 1H) 8.26 (s, 1H) 8.28 (d, J=8.34 Hz, 1H) 8.75 (d,J=7.07 Hz, 1H). [M+H] calc'd for C₂₄H₂₉F₂N₇O₃, 502. found 502.

Compound 160:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(methylsulfonyl)azetidin-3-yl)benzamide

To a solution ofN-(azetidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide(100 mg, 0.19 mmol) in DCM (2.5 mL, 1:2:2) was added DIEA (50 μL, 0.285mmol), followed by methanesulfonyl chloride (23 μL, 0.21 mmol). Afterstirring overnight the solvent was removed and the product purified byreverse phase HPLC, free based, and lyophilized to yield a white solid(9.3 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.79 (m, 6H) 1.96(br. s., 2H) 3.05 (s, 3H) 3.92 (s, 3H) 3.94 (d, J=1.77 Hz, 2H) 4.03-4.15(m, 4H) 4.61-4.72 (m, 1H) 4.76-4.87 (m, 1H) 7.24 (d, J=6.57 Hz, 1H) 8.08(s, 1H) 8.27 (d, 1H) 8.31 (s, 1H) 8.73 (d, J=3.79 Hz, 1H). [M+H] calc'dfor C₂₅H₃₀F₃N₇O₅S, 598. found 598.

Compound 161:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(piperidin-4-yl)azetidin-3-yl)benzamide

To a solution of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl4-(3-aminoazetidin-1-yl)piperidine-1-carboxylate (72 mg, 0.25 mmol),HATU (125 mg, 0.33 mmol), and DIEA (80 μL, 0.44 mmol). The reactionmixture was stirred for 1 h. It was then poured into 100 mL of rapidlystirring water. A white solid forms and was filtered, washed with waterand dried. This solid was treated with TFA in DCM (3 mL 1:1) for 2 days.The solvent was then removed, and the product purified by reverse phaseHPLC, free based and lyophilized to yield a white solid (17.8 mg, 14%yield ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (br. s., 2H) 1.50-1.79 (m,9H) 1.93 (br. s., 2H) 2.07 (br. s., 1H) 2.35-2.44 (m, 2H) 2.85-3.00 (m,4H) 3.52 (t, J=7.20 Hz, 2H) 3.94 (s, 3H) 4.05 (t, J=14.02 Hz, 2H)4.37-4.50 (m, 1H) 4.68-4.84 (m, 1H) 7.47-7.52 (m, 2H) 7.98 (s, 1H) 8.26(s, 1H) 8.29 (d, 1H) 8.61 (d, J=6.57 Hz, 1H). [M+H] calc'd forC₂₉H₃₈F₂N₈O₃, 585. found 585.

Compound 162:4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-(1-(cyclopropylmethyl)piperidin-4-yl)azetidin-3-yl)-3-methoxybenzamide

To a solution of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(piperidin-4-yl)azetidin-3-yl)benzamide(13 mg, 0.023 mmol) in MeOH (2.5 mL) was added AcOH (0.03 mL),cyclopropane aldehyde (3 μL, 0.034 mmol), borane-pyridine complex (10μL, 0.08 mmol), and left to stir overnight. The solvent was then removedand the product purified by reverse phase HPLC, free based, andlyophilized to yield a white solid (6.4 mg, 44%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm −0.03-0.14 (m, 3H) 0.34-0.51 (m, 2H) 0.80 (s, 1H) 1.17(d, J=2.53 Hz, 2H) 1.60 (br. s., 6H) 1.71 (br. s., 2H) 1.94 (br. s., 5H)2.13 (d, J=6.32 Hz, 2H) 2.82 (br. s., 2H) 2.96 (t, J=7.20 Hz, 2H) 3.52(t, J=7.20 Hz, 2H) 3.92 (s, 1H) 4.05 (t, J=14.02 Hz, 2H) 4.38-4.50 (m,1H) 4.70-4.82 (m, 1H) 7.41-7.58 (m, 2H) 7.98 (s, 1H) 8.22-8.33 (m, 2H)8.61 (d, J=6.57 Hz, 1H). [M+H] calc'd for C₃₃H₄₄F₂N₈O₃, 638. found 638.

Compound 163:4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Ethyl 2,2-difluoro-3-(isopropylamino)propanoate: Ethyl3-(dibenzylamino)-2,2-difluoropropanoate (5.00 g, 15.0 mmol) wasdissolved in EtOH (25 mL) and trifluoroacetic acid was added (1.15 mL,15.5 mmol). To this mixture, Pd(OH)₂/C (20%, 250 mg) was added, and thereaction mixture was hydrogenated at 60 psi overnight. The mixture wasfiltered through a pad of Celite, the Celite pad was washed with ethanoland the filtrate was concentrated in vacuo. The residue was dissolved inTHF (65 mL) and to the solution was added acetone (0.872 g, 15.0 mmol)and sodium acetate (1.23 g, 15.0 mmol). The reaction mixture was cooledto 0° C. and NaBH(OAc)₃ (4.77 g, 22.5 mmol) was added in portions over 5min. The mixture was stirred vigorously at room temperature overnightand then was poured into a cold (0° C.) brine solution (100 mL). The pHwas adjusted to 12.5 with NaOH (50%) and the mixture was extracted withethyl acetate (3×50 mL). The combined organic extract were dried (MgSO₄)and concentrated in vacuo to afford the title compound as a clear lightyellow oil (1.54 g, 54%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d,J=6.32 Hz, 6H) 1.36 (t, J=7.20 Hz, 3H) 2.73-2.94 (m, 1H) 3.20 (t,J=13.52 Hz, 2H) 4.34 (q, J=7.24 Hz, 2H)

Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate:Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) wasdissolved in acetone and K₂CO₃ (2.12 g, 15.3 mmol) was added. Thesolution was purged with nitrogen gas and cooled to 0° C. A solution of2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL)was added dropwise at 0° C. over 1 h. The reaction mixture was allowedto slowly warm to room temperature and stirred overnight. It was dilutedwith dichloromethane (50 mL) and filtered thru a celite plug. Thefiltrate was concentrated in vacuo and the residue purified by flashcolumn chromatography on silica gel (120 g SiO₂, hexanes:ethyl acetate10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6H) 1.34 (t,J=7.20 Hz, 3H) 3.63-3.75 (m, 1H) 4.24 (t, J=13.14 Hz, 2H) 4.34 (q,J=7.07 Hz, 2H) 8.74 (s, 1H).

2-chloro-7,7-difluoro-9-isopropyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:Ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(isopropyl)amino)-2,2-difluoropropanoate(1.90 g, 5.39 mmol) was dissolved in HOAc (10 mL) and HCl (conc, 3.1mL). Iron (0.610 g, 10.9 mmol) was added and the rm was stirred at rtfor 3 h and at 60° C. overnight. The mixture was diluted with water andextracted with ethyl acetate. The combined organic extracts were dried,filtered and concentrated in vacuo. The residue was purified using flashcolumn chromatography on silica gel (40 g SiO₂, hexanes:ethyl acetate2:1-1:1) to afford the title compounds as a light yellow solid (0.809 g,54%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (d, J=6.82 Hz, 6H) 3.42(s, 3H) 3.89 (t, J=12.38 Hz, 2H) 4.97-5.10 (m, 1H) 8.06 (s, 1H).

2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one:2-chloro-7,7-difluoro-9-isopropyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(0.800 g, 2.89 mmol) was dissolved in DMA (7 mL) and cooled to 0° C.under nitrogen. NaH (140 mg, 3.50 mmol) was added, the mixture wasstirred for 20 min and MeI (0.23 mL, 3.61 mmol) was added dropwise. Thereaction mixture was stirred at room temperature for 1 h and quenchedwith water (25 mL). The pH was adjusted to 1 (aq. HCl) and the mixturewas extracted with ethyl acetate (4×20 mL). The comb organic extractswere concentrated in vacuo, dissolved in dichloromethane/trifluoroaceticacid (5:1, 6 ml) and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (80 g SiO₂, hexanes:ethylacetate 1:1) to afford the title compound as a yellow solid (0.753 g,90%).

2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(100 mg, 0.344 mmol) and4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (95.0 mg, 0.361mmol) were suspended in water (2 mL) and sulfuric acid (118 mg, 1.20mmol) was added. The reaction mixture was stirred in a closed vial at100° C. for 18 h, cooled, diluted with water (8 mL) and brought to pH=7using solid Na₂CO₃. The resulting mixture was diluted with ethanol (0.5mL) and stirred for 5 min. The precipitate was filtered and dried in airfor 20-30 min. I was then suspended in ethanol (−10 mL), treated withsolid sodium bicarbonate (350 mg) and stirred vigorously for 1 h. Theinsoluble salts were filtered off and filtrate was concentrated invacuo. The residue was crystallized from ethanol-water (1:10; 11 mL) anddried in vacuum to afford the title compound as a white solid (115 mg,65%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (d, J=6.82 Hz, 6H) 1.52-1.65(m, 2H) 1.70-1.80 (m, 2H) 1.87-1.97 (m, 2H) 2.17 (s, 3H) 2.78 (d,J=11.62 Hz, 2H) 3.32 (s, 3H) 3.64-3.82 (m, 1H) 3.94 (s, 3H) 4.04 (t,J=13.52 Hz, 2H) 4.88 (spt, 1H) 7.46-7.54 (m, 2H) 7.88 (s, 1H) 8.11 (d,J=7.83 Hz, 1H) 8.22 (s, 1H) 8.30 (d, J=8.34 Hz, 1H); [M+H] calc'd forC₂₅H₃₃F₂N₇O₃, 518. found 518.

Compound 164:4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(100 mg, 0.344 mmol) and4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (100 mg,0.355 mmol) were suspended in water (2 mL) and sulfuric acid (118 mg,1.20 mmol) was added. The reaction mixture was stirred in a closed vialat 100° C. for 18 h, cooled, diluted with water (5 mL) and brought topH=7 using solid sodium carbonate. The resulting mixture was dilutedwith ethanol (0.5 mL) and stirred for 5 min. The precipitate wasfiltered, washed with water (5 mL) and dried in air for 20-30 min. Itwas then suspended in ethanol (˜10 mL), treated with solid sodiumbicarbonate (130 mg) and stirred vigorously for 45 min. The insolublesalts were filtered off and filtrate was concentrated in vacuo. Theresidue was crystallized from ethanol-water (1:7; 8 mL) and dried invacuum to afford the title compound as a white solid (65 mg, 35%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.26 (d, J=6.82 Hz, 6H) 1.49-1.62 (m, 2H)1.77 (br. d., 2H) 1.95 (app. t, J=11.2 Hz, 2H) 2.15 (s, 3H) 2.73 (br.d., J=11.12 Hz, 2H) 3.33 (s, 3H) 3.71 (m, J=7.83 Hz, 1H) 3.91 (s, 3H)4.07 (t, J=13.52 Hz, 2H) 4.90 (m, 1H) 7.19 (d, J=6.57 Hz, 1H) 7.88 (dd,J=7.33, 3.03 Hz, 1H) 7.97 (s, 1H) 8.20-8.32 (m, 2H); [M+H] calc'd forC₂₅H₃₂F₃N₇O₃, 536. found 536.

Compound 165:N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzamide

The title compound was prepared using Buchwald reaction from2-chloro-7,7-difluoro-9-isopropyl-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(573 mg, 1.98 mmole) and4-amino-N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-2-fluoro-5-methoxybenzamide(958 mg, 2.372 mmole) and the final product was purified by reversephase HPLC and basified to give the free base. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.53 (br. s, 2H) 0.88 (br. s., 2H) 1.34 (d, J=6.82Hz, 8H) 1.57 (s, 6H) 1.98 (br. s., 2H) 2.19 (br. s., 6H) 2.67 (br. s.,6H) 3.41 (s, 3H) 3.80-4.10 (m, 4H) 4.88-5.09 (m, 1H) 6.60 (dd, J=15.16,7.83 Hz, 1H) 7.56 (d, J=7.07 Hz, 1H) 7.78 (s, 1H) 8.04 (s, 1H) 8.37 (d,J=15.16 Hz, 1H). [M+H] calc'd for C₃₃H₄₅F₃N₈O₃, 659. found 659.

Compound 166:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (241 g, 0.72 mol) wasdissolved in EtOH (1 L) and then 20% Pd(OH)₂/C (24 g) andtrifluoroacetic acid (60 mL, 0.78 mol) were added. The vessel wasrepeatedly purged with hydrogen three times and then left under hydrogen(60 psi, 413 kP) and shaken overnight. The mixture was filtered througha pad of Celite®, washed with ethanol and the filtrate was concentratedwithout heating to give 200 g of compound ethyl3-amino-2,2-difluoropropanoate which contained a little bit of ethanol.

To a solution of ethyl 3-amino-2,2-difluoropropanoate (401 g, 1.5 mol),cyclopentanone (140 mL, 1.575 mol) and sodium acetate (123 g, 1.5 mol)in THF (6.5 L) was added NaBH(OAc)₃ (477 g, 2.25 mol) portionwise over aperiod of 40 min in ice bath. The resulting mixture was stirredvigorously at room temperature overnight. The mixture was added slowlyto a stirring solution of ice (3300 mL), saturated aqueous sodiumbicarbonate (3300 mL) and ethyl acetate (3300 mL) cooled in ice-saltbath over a period of 30 min. At this time the layers were separated andthe pH of aqueous phase was further adjusted to 11 by addition of 25%aqueous NaOH while cooling in the bath. The aqueous phase was extractedwith ethyl acetate (3.5 L×2) and all organic layers were combined,washed with cold saturated NaHCO₃ (1.5 L×2), brine (1.5 L), dried overMgSO₄, filtered and concentrated to give 280 g of ethyl3-(cyclopentylamino)-2,2-difluoropropanoate.

To a 12 L three-necked flask were charged with ethyl3-(cyclopentylamino)-2,2-difluoropropanoate (268 g, 1.21 mol) andacetone (2.7 L) and the solution was cooled in ice-salt bath. Thenpotassium carbonate (337 g, 2.44 mol) was added followed by addition ofa solution of 2,4-dichloro-5-nitropyrimidine (260 g, 1.34 mol) inacetone (1.3 L) over a period of 1 h. The resulting mixture was allowedto warm to room temperature slowly and stirred overnight which wasmonitored by LC-MS. The solvent was removed on rotavapor and theresulting residue was redissloved in water (2 L) and ethyl acetate (2L). After separation, the aqueous phase was extracted with ethyl acetate(2 L×2) and all organic extracts were combined, washed with water (2 L),brine (2 L), dried over MgSO₄ and concentrated. The resulting solid waspurified by column chromatography (eluting with hexanes/ethylacetate=20/1, 15/1 then 10/1) to give 289 g of compound ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate.

To a solution of ethyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate(289 g, 0.763 mol) in acetic acid (1.75 L) in ice bath was added ironpowder (86 g, 1.53 mol) followed by addition of conc. HCl (435 mL) overa period of 30 min. The resulting mixture was continued to stir in icebath for 10 min and then transferred to heating mantle and heated to 60°C. which was monitored by LC-MS. After 5 h, the mixture was concentratedby about 75% and the residue was poured into 3.5 L of ice water and 3.5L of ethyl acetate. After separation, the aqueous phase was extractedwith ethyl acetate (4 L×2) and all organic extracts were combined,washed with saturated sodium bicarbonate (2.5 L), brine (2.5 L), driedover anhydrous sodium sulfate and concentrated. The resulting residuewas triturated with ethyl acetate (420 mL) and diethyl ether (3 L) togive 169 g of compound2-chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(100 g, 0.33 mol) was dissolved in DMA (700 mL) and cooled in ice bathunder nitrogen. NaH (14.35 g, 60% in mineral oil, 0.363 mol) was addedportionwise over a period of 20 min and the resulting mixture wascontinued to stir in ice bath for 10 min. Then iodomethane (21 mL, 0.363mol) was added over a period of 10 min in ice bath and the mixture wasstirred in ice bath for 10 min and then allowed to warm to roomtemperature and stirred for 1 h. The mixture was poured into ice water(2.5 L) and the resulting solid was filtered, washed with water, driedto give 98 g of2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

A mixture of2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(98 g, 0.31 mol), 3-methoxy-4-aminobenzoic acid (57 g, 0.341 mol) ini-PrOH (1.05 L) and conc. HCl (30 mL) was heated to reflux for a day.The mixture was cooled to room temperature and the solid was filtered,washed with isopropanol and dried to give 96.5 g of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid.

A mixture of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (96.5 g, 0.216 mol), N-methyl-4-aminopiperidine (29.3 g, 0.259mol), HOBt (35 g, 0.259 mol), diisopropylethylamine (45 mL, 0.259 mol)in anhydrous DMF (2.6 L) was cooled in ice bath under nitrogen. EDCI(49.8 g, 0.259 mol) was added and the resulting mixture was allowed towarm to room temperature and stirred overnight. The mixture was pouredinto ice water (8 L) and ethyl acetate (3 L) and separated. The aqueousphase was extracted with ethyl acetate (4 L×2) and all organic extractswere combined, washed with water, brine, dried over MgSO₄ andconcentrated. The resulting solid was triturated with diethyl ether togive 47 g of the title compound. DSC peak at 241.42° C.

Compound 167:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(3598 g, 11.89 mol) was dissolved in NMP (11.108 kg) and cooled to about−3° C. A 1 M solution of NaAHMDS (11.919 kg, 1.1 eq.) was added over aperiod of 80 minutes maintaining the temperature below 4° C. Iodomethane(1.858 kg) was added over a period of 10 minutes maintaining thetemperature below 35° C. The addition funnel was washed with THF. Thetemperature was adjusted to 20 to 25° C. and the reaction mixture wasstirred for 3 hours. A 1 M solution of NaHMDS (1.2 kg) was added at 23°C. followed by iodomethane (0.188 kg). The addition funnel was washedwith THF. The temperature was adjusted to 20 to 25° C. and the reactionmixture was stirred overnight. The temperature was adjusted to 10° C.,concentrated aqueous hydrochloric acid (6.42 L), the THF was removed bydistillation at reduced pressure, the temperature was adjusted to 20°C., and water (53.31 kg) was slowly added over about 60 minutesmaintaining the temperature at about 23 to 25° C. The temperature wasadjusted to about 10° followed by stirring overnight. The reactionmixture was filtered, the filter cake was washed with isopropylalcohol/water (1:1, 2×2 L), and dried in by a stream of nitrogen. Thefilter cake was dissolved in isopropyl alcohol (4.17 kg) at 76° C.,water (20.70 kg) was slowly added over about 85 minutes maintaining thetemperature at about 73 to 76° C., after 20 minutes cooled to about 11°over about 3 hours and stir overnight. Collect the solid by filtration,rinse with isopropyl alcohol/water (1:1, 2×1.7 L), and dry under astream of nitrogen, followed by drying in an oven for 4 days to give2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

A mixture of2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(2.542 kg, 8.05 mol), 3-methoxy-4-aminobenzoic acid (1.50 kg) in t-butylalcohol (23 L) and heat to about 53° C. Add conc. HCl (951 g) over about10 minutes, heat to 80° C. and stir for 60 hours. The temperature wasadjusted to 15° C. and stirred for 40 hours to give a solid which wascollected by filtration, rinsed with isopropyl alcohol/water (1:1, 2×2.5L) and dried under a stream of nitrogen for about 1.5 hours, then in avacuum oven at 40° C. for 4 days to give4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid.

A mixture of4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (5.125 kg, 6.51 mol), dichloromethane (12 kg), and NMP (0.058 L,0.09 eq.) was adjusted to 18° C. Thionyl chloride (1.868 kg, 2.4 eq.)was added over about 10 minutes, and each reaction was stirred at about18 to 19° C. for 17.5 hours. The temperature was adjusted to 25° C. andthe reaction was stirred for 7 hours, adjusted to 18 to 20° C. andstirred for overnight, then 2 days. The dichloromethane was removed bydistillation at reduced pressure, toluene (6.2 kg) was added and thedistillation continued. About 6 L of dichloromethane were removed.Toluene (6.18 L) was added, the temperature was adjusted to about 20 to25° C., and a suspension was stirred overnight. The solid was collectedby filtration, rinsed with toluente (2×2.12 kg), dried for 3.5 hours ina stream of nitrogen, and then in a vacuum oven at 40° C. for 2 days togive4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid.

Combine4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoicacid (3.108 kg, 6.17 mol) and acetonitrile (14.56 kg) and adjust thetemperature to about 0° C. Add N-methyl-4-aminopiperidine (0.775 k, 1.1eq.). Diisopropylethylamine (1.595 kg) was added aver about 29 minutesat temperature of about 6 to 12° C., the temperature was adjusted toabout 20 to 25° C. and the reaction mixture was stirred overnight. Thesolid was collected by filtration, rinsed with acetonitrile (4.47 kg)and dried under at stream of nitrogen for 1 hour, then in a vacuum ovenat 40° C. for 2 days to give the title compound.

The title compound (3.35 kg), ethyl alcohol (10.65 kg), and aqueous 2Nhydrochloric acid solution were combined at about 20° C. and filtered.Aqueous 2N sodium hydroxide was added and the reaction mixture wasstirred at about 20 to 25° C. overnight. Crystals (0.5 g) similar to theones obtained in Compound 166 were added and the stirring continued for24 hours. Water (5.39 kg) was added and the suspension stirred for 4hours, filtered, rinsed with water (1.7 kg) and ethyl alcohol (1.7 kg),dried with a stream of nitrogen, and then in a vacuum oven at 40° C. for3.8 days to give the title compound. DSC peak at 242.12° C.

Compound 168:4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide

2-Fluoro-5-methoxy-4-nitrobenzoic acid: To a solution of2,5-difluoro-4-nitrobenzoic acid (55 g, 291 mmol) in methanol (800 mL)at 80° C. was added a methanolic solution of potassium hydroxide (48.9g, 873 mmol in 175 mL MeOH, pre-heated at 80° C. to dissolve) dropwisein a period of 2 h using an addition funnel. The reaction mixture wascontinuously stirred for 1 h after addition was completed. It was thenconcentrated, acidified with HCl to pH=1-2. The reaction mixture wasthen vigorously stirred overnight. Fine powder was filtered, washed withmore water and dried to give the product as light yellow powder (55.4 g,90%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (s, 3H) 7.66 (d, J=4 Hz, 1H)8.01 (d, J=8 Hz, 1H). [M+H] calc'd for C₈H₆FNO₅, 216. found 216.

2-Fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide: To amixture of 2-fluoro-5-methoxy-4-nitrobenzoic acid (53.8 g, 250 mmol),1-methylpiperidin-4-amine (31.4 g, 275 mmol), DIEA (134 mL, 750 mmol) in1 L of DCM at 0° C. was added HATU (114 g, 300 mmol) in four batches.The reaction mixture was stirred at room temp. for 16 h. After which, itwas concentrated and diluted to IL of a mixture of MeOH in water (5%).The suspension was stirred vigorously for 2 h until seen a suspension offine powder. The solid was filtered, washed with more water and dried togive 55 g of light yellow product. The filtrate was extracted withEtOAc, concentrated and re-suspended in water (5% of MeOH) and repeatingthe same procedure as above, after which another batch of solid wasobtained (total 67 g, 86%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (m, 2H)1.81 (m, 2H) 2.04 (m, 2H) 2.19 (s, 3H) 2.77 (d, J=8 Hz, 2H) 3.73 (m, 1H)3.94 (s, 3H) 7.42 (d, J=5.6 Hz, 1H) 7.98 (d, J=8.8 Hz, 1H) 8.51 (d,J=7.6 Hz, 1H). [M+H] calc'd for C₁₄H₁₈FN₃O₄, 312. found 312.

4-Amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide: To asolution of2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g,177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mLof concentrated HCl. The reaction mixture was hydrogenated using ahydrogen balloon for 22 h. The solution was filtered through celite andconcentrated to a minimum volume, after which solid was filtered, washedwith ether. The filtrate concentrated again and trituated with EtOH andrepeated several times to get out more products. The solid was combinedand further dried to give total 50 g of product as light yellow powder(>98%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.64-2.02 (m, 4H) 2.61 (s, 3H) 2.90(t, J=11.0 Hz, 2H) 3.24 (m, 2H) 3.72-3.81 (m, 3H) 3.84-4.03 (m, 1H) 5.60(s, 2H) 6.29-6.50 (m, 1H) 7.01 (d, J=6.8 Hz, 1H) 7.69 (dd, J=7.3, 4.8Hz, 1H). [M+H] calc'd for C₁₄H₂₀FN₃O₂, 282. found 282.

4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide:A mixture of2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(25 g, 79.1 mmol),4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide (23.3 g,83 mmol), isopropanol (197 ml), and concentrated hydrochloric acid (8mL) was stirred in an oil bath of 100° C. (temp. inside the flask was83° C.) for 3 days (lots of precipitate appeared after first day ofstirring). The reaction mixture was cooled down and the white solid wasfiltered and washed with more iPrOH, finally dried to give 40 g tansolid as HCl salt.

Above obtained HCl salt (40 g) was dissolved in 1 L of MeOH with aneffective stirring bar. It was cooled to 0° C., sodium bicarbonate solid(28.1 g, 0.33 mol) was added slowly. The reaction mixture was thenstirred at r.t for 4 h. After which, it was filtered through a pad ofcelite. The filtrate concentrated in vacuo to 500 mL in volume, and 500mL of water was charged into the flask. The mixture was then kept onrotavaping at 20° C. Lots of pinkish precipitate appeared. Until around100 mL of MeOH left, 500 mL more of water was added to the flask. Thewhole was filtered, solid washed with more water (500 mL) and dried togive 35 g of product as light pinkish solid (>99% pure by LC).

To a 500 mL round bottom flask, was added 60 g of the free base and EtOH(200 ml). It was heated at 85° C. for 0.5 h. It was then cooled down,solid filtered and washed with more EtOH (200 mL). When dried, around 48g of off-white solid was obtained (filtrate contained color and someimpurities). The solid was then completely dissolved in 4 L of MeOH,filtered on the paper. The filtrate was concentrated to a solid. It wasthen dissolved in 200 mL of EtOH. The suspension was then heated at 60°C. with effective stirring for 24 h. The slurry was then cooled downgradually to room temperature, filtered. The solid was washed with moreEtOH (200 mL), dried in a vacuum oven (60° C.) for 3 days. Finally, 44 gof product as white solid was obtained (73% recovery). The combinedfiltrate (contained mostly product) was concentrated and set aside forfurther purification by prep-HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.47-1.82 (m, 10H) 1.90-2.04 (m, 4H) 2.16 (s, 3H) 2.74 (d, J=11.6 Hz,2H) 3.63-3.77 (m, 1H) 3.92 (s, 3H) 4.09 (t, J=13.9 Hz, 2H) 4.82 (m, 1H)7.19 (d, J=6.8 Hz, 1H) 7.91 (dd, J=7.7, 3.4 Hz, 1H) 8.04 (d, J=1.3 Hz,1H) 8.25 (d, J=13.4 Hz, 1H) 8.31 (s, 1H). Melting point 194.5-195.5° C.[M+H] calc'd for C₂₇H₃₄F₃N₇O₃, 562. found 562.

In addition to the foregoing, the above reaction schemes and variationsthereof have been used to prepare the following compounds:

Further, the following compounds can be prepared using variations of theprocedure described in connection with Scheme 15.

In addition, the following compounds can be prepared using variations ofthe procedure described in connection with Scheme 16.

Biological Testing

PLK Activity

The activity of compounds as PLK inhibitors may be assayed in vitro, invivo or in a cell line. Provided below is an in vitro enzymatic activityassay for activity against PLK1.

Purified PLK1 may be obtained as follows. cDNA encoding human PLK1 (SEQID No. 1, Accession Number: NM_(—)005030) was isolated by polymerasechain reaction (PCR) with primers (SEQ ID Nos. 2 and 3) and cloned intopcDNA4/His-Max-TOPO (Invitrogen, USA) according to the manufacturer'smanual. PCR was performed using the vector as a template. In the PCR,primers containing sequences encoding a FLAG-tag (DYKDDDDK) in theamino-terminal region (SEQ ID No. 4) and vector sequence (SEQ ID No. 5)were used. After XbaI and XhoI digestion of the PCR product, thefragment was subcloned into pFASTBAC1 (Invitrogen, USA). Recombinantbaculoviruses were prepared according to the procedure of the Bac-to-Bacbaculovirus expression system (Invitrogen, USA). Sf21 cells werepurchased from Invitrogen and grown in Sf-900 II SFM medium containing10% fetal bovine serum, 50 μg/mL gentamicin and 0.1% pluronic F-68(Invitrogen, USA) at 28° C. For preparation of PLK1 enzyme, Sf21 cellswere infected with recombinant baculoviruses and cultured at 28° C. for72 h. Cells were lysed and FLAG-tagged PLK1 protein (SEQ ID No. 6) waspurified by affinity chromatography using anti-FLAG M2 affinity gel(Sigma, USA).

It should be noted that a variety of other expression systems and hostsare also suitable for the expression of PLK1, as would be readilyappreciated by one of skill in the art.

The inhibition of PLK1 by the compounds was determined with thefollowing assay that measures the phosphorylation of alpha casein byrecombinant PLK1. Kinase reactions were performed at room temperaturefor 40 min in the kinase reaction buffer (25 mmol/L HEPES, pH 7.5, 10mmol/L magnesium acetate, 1 mmol/L dithiothreitol) containing 50 ng PLK1enzyme, 0.1 μCi [γ-³²P]ATP, 500 nmol/L ATP and 3 μg alpha casein (MPBiomedicals Inc., USA) in a final volume of 50 μL. The incubation wasterminated by the addition of 10% trichloroacetic acid (Wako, Japan).Phosphorylated proteins were filtrated in GF/C filter plates (Packard,USA) with a Cell harvester (Packard, USA) and washed out free[γ-³²P]-ATP with 250 mmol/L phosphoric acid. Then, the plates were airdried for 60 min at 45° C., followed by the addition of 20 μL ofMicroScint-O (Packard, USA). The radioactivity was counted by aTop-count scintillation counter (Packard, USA). The IC₅₀ values for testcompounds were calculated by Prism 3.02 (GraphPad Software, USA).

The cell culture and proliferation assay may be carried out as follows:the HT29 human colorectal adenocarcinoma cell line (ATCC, USA) wasmaintained in Dulbecco's Modified Eagle's Medium (Invitrogen, USA)supplemented with 10% fetal bovine serum (JRH, USA). The cellproliferation assay was carried out with the Cell Titer-Glo luminescentcell viability assay (Promega, USA) according to the manufacture'sinstruction after the 72 hr treatment of the cells in the presence ofthe compounds. The cell viability was shown as a percentage of DMSOtreated cells. The IC₅₀ values for the compounds were calculated byPrism 4 (GraphPad Software, USA).

For analysis of the cell cycle distribution and the phosphorylation ofhistone H3, the cells were harvested and fixed with ice-cold 70% ethanolafter the 48 hr treatment of the cells in the presence of the compounds.The cells were washed twice with PBS containing 2% FCS (JRH), thenincubated with Alexa Flour 647-conjugated anti-phospho-histone H3antibody (Cell signaling, USA) and RNase (Invitrogen) for 30 min at roomtemperature. After washing twice with PBS containing 2% FCS, the cellswere counterstained with propidium iodide. The cell cycle distributionand phosphorylation of histone H3 were analyzed using the FACSCalibursystem (BD Bioscience, San Jose, Calif., USA,).

The activity of compounds as PLK inhibitors can be assessed in vivousing BALB/cA Jcl-nu/nu mice bearing the HCT116 or the HT29 cellsinoculated subcutaneously in axillary area. The growth retardation maybe determined, for example, by caliper measurements of the tumor volume.

pIC₅₀ values may be calculated by non-linear curve fitting of thecompound concentrations and fluorescence intensities to the standardpIC₅₀ equation. pIC₅₀ values for the cell proliferative assay of selectcompounds of the present invention are given in Table 1.

TABLE 1 Compound pIC₅₀ (PLK1) 2 <8.7 3 ≧8.7 4 ≧8.7 5 ≧8.7 7 <8.7 8 ≧8.79 ≧8.7 10 ≧8.7 11 ≧8.7 12 <8.7 14 ≧8.7 15 ≧8.7 17 <8.7 18 <8.7 19 <8.720 <8.7 21 <8.7 22 ≧8.7 23 ≧8.7 24 <8.7 25 <8.7 26 <8.7 27 ≧8.7 28 <8.729 <8.7 30 <8.7 31 ≧8.7 33 ≧8.7 34 ≧8.7 35 ≧8.7 36 ≧8.7 37 <8.7 38 ≧8.739 <8.7 40 ≧8.7 41 ≧8.7 42 ≧8.7 43 ≧8.7 44 ≧8.7 45 ≧8.7 46 <8.7 47 ≧8.748 ≧8.7 49 ≧8.7 50 ≧8.7 51 ≧8.7 52 <8.7 54 <8.7 56 <8.7 57 <8.7 58 ≧8.760 ≧8.7 61 ≧8.7 62 ≧8.7 63 ≧8.7 64 ≧8.7 65 ≧8.7 66 ≧8.7 67 ≧8.7 69 ≧8.770 ≧8.7 71 ≧8.7 72 ≧8.7 73 ≧8.7 74 ≧8.7 75 ≧8.7 76 ≧8.7 77 ≧8.7 78 ≧8.779 ≧8.7 80 ≧8.7 81 ≧8.7 83 ≧8.7 84 ≧8.7 85 <8.7 87 ≧8.7 88 ≧8.7 89 ≧8.790 ≧8.7 92 <8.7 95 ≧8.7 96 <8.7 97 <8.7 99 ≧8.7 100 ≧8.7 101 <8.7 102≧8.7 103 <8.7 104 <8.7 105 ≧8.7 106 <8.7 107 <8.7 109 ≧8.7 110 <8.7 111≧8.7 113 ≧8.7 114 <8.7 115 <8.7 116 ≧8.7 117 ≧8.7 118 <8.7 119 <8.7 120<8.7 122 <8.7 123 <8.7 124 <8.7 125 ≧8.7 126 <8.7 127 ≧8.7 128 ≧8.7 129≧8.7 130 ≧8.7 131 ≧8.7 132 ≧8.7 133 ≧8.7 134 <8.7 135 <8.7 136 <8.7 137<8.7 138 <8.7 139 <8.7

Drug Resistance

P-glycoprotein (PgP, MDR1) overexpression has been shown to becorrelated with resistance to anti-cancer agents such as taxanes andanthracyclines. Accordingly, development of compounds that are notsusceptible to PgP may be capable of overcoming drug-resistance incancer (Nat Rev Drug Discov., 2006 March; 5(3): 219-34).

To assess whether compounds are susceptible to PgP, in vitro growthinhibitory assays were performed using MES-SA and its derivativeMES-SA/Dx5, which are known to be anthracycline resistant cell linesthat overexpress PgP (Anticancer Res., 2005 January-February; 25(1A):383-9). Cells were seeded at 1000 cells/well in McCoy's 5A medium(Invitrogen) with 10% FCS in 96-well plates (Falcon). After 24 hours,compounds were added to the cell culture medium at the finalconcentrations of 1000, 300, 100, 30, 10, 3, 1, 0.3 and 0.1 nM. Cellviability was quantified using CellTiter-Glo kits (Promega) after threedays of incubation. The IC₅₀ of each compound was calculated usingGraphPad software (Prism). The IC₅₀ values for select examples are shownin Table 2. The data is reported as the ratio of the IC₅₀ value for theMES-SA/Dx5 assay to the IC₅₀ value for the MES-SA assay.

TABLE 2 IC₅₀ (MES-SA/Dx5; nM)/ Compound No. IC₅₀ (MES-SA; nM) 3 31.910 >15.1 116 1.9 117 12.5 113 2.5 131 2.5

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

1. The compound4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamideor a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable excipient.